ORIGINAL ARTICLE

Encapsulated apocrine papillary carcinomaof the breast—a tumour of uncertain malignantpotential: report of five cases

Melanie Seal & Christine Wilson & Gregory J. Naus &

Stephen Chia & Terry C. Bainbridge & Malcolm M. Hayes

Received: 4 June 2009 /Revised: 24 August 2009 /Accepted: 1 September 2009 /Published online: 28 October 2009# Springer-Verlag 2009

Abstract Five cases of an unusual encapsulated apocrinepapillary tumour are reported. All presented as cysticmasses in the breast of women aged 44–84 years. Imagingstudies showed a complex cyst often with one or moremural nodules. The key histological features are similar tothose of classical encapsulated papillary carcinoma in thatmyoepithelial cells were absent within the papillarystructures and at the periphery of the cyst. All were pureapocrine in type and showed variable degrees of cytologicalatypia and mitotic activity. All lacked evidence of malig-nancy in the breast tissue outside of the lesion. Sentinellymph node biopsies performed in three of the cases werenegative for metastases, and all have behaved in a benignfashion.

Keywords Breast neoplasms . Intracystic . Apocrine .

Papillary carcinoma

Introduction

Encapsulated papillary carcinoma (intracystic) of the breast(EPC) is a rare entity representing approximately 0.5–2.0%of all breast tumours [1]. Traditionally considered to be avariant of ductal carcinoma in situ (DCIS) characterised bypapillary carcinoma within a cystically dilated duct, manyauthors now believe these tumours have malignant poten-tial. This is based on evidence that they lack a myoepithe-lial cell layer at their periphery which pathologists considera determinant for invasion. Furthermore, there have beencase reports of intracystic papillary tumours metastatic toaxillary lymph nodes and distant sites [1–3].

We present five cases of encapsulated apocrine papillarycarcinoma of the breast and evaluate the clinical outcome ofthese patients. The objectives of this study are to describe theclinical, radiological, and pathological findings of these raretumours and to discuss their malignant potential. Our goal isto aid clinicians and pathologists to make treatment decisionsfor patients who present with this diagnostic challenge.

Materials and methods

The clinical records, radiographical images, and pathologyslides from five patients with suspected EPC of apocrine typeseen during 1995–2009 at our centre were reviewed. Fullethics approval was obtained before commencing study.

Hematoxylin and Eosin (H&E) stained slides wereavailable in all cases, and blocks were obtained forimmunostaining of myoepithelial cells using a VentanaBenchmark XT autostainer. The antibodies used andstaining protocols are summarised in Table 1.

M. Seal : S. ChiaThe Department of Medical Oncology,British Columbia Cancer Agency,Vancouver, Canada

G. J. Naus : T. C. Bainbridge :M. M. Hayes (*)The Department of Pathology, British Columbia Cancer Agency,Vancouver V5Z 4E6, Canadae-mail: mhayes@bccancer.bc.ca

C. WilsonThe Department of Medical Imaging,British Columbia Cancer Agency,Vancouver, Canada

Virchows Arch (2009) 455:477–483DOI 10.1007/s00428-009-0834-7

Results

Clinical data

The clinical details are summarised in Table 2. All patientsunderwent partial mastectomy, and three had sentinellymph node procedures. One patient received radiotherapyto the breast. None received systemic therapy. Althoughfour patients had further biopsies, all were negative formalignancy, and no patient had recurrence. The length offollow-up in each case is given in Table 2.

Breast imaging

Mammograms were obtained in all cases. Four of the fivepatients showed soft tissue masses ranging in size from 3 to12 cm (Fig. 1). Ultrasound examination showed a complexcyst with a mural nodule or intracystic papillary lesion infour patients. These nodules measured between 8 and16 mm (Fig. 2). One case showed pleomorphic calcifica-tions within the mass located in the cyst. One patient hadmultiple mural nodules with increased vascularity seen onDoppler ultrasound within them.

Antibody Clone Dilution Antigen retrieval Indicator

P63 4A4 Dako 1:100 CCI-mild VU-DAB

HCM SMMS-1 Dako 1:50 CCI-standard VU-DAB

CD10 56C6 Novo Castra 1:25 CCI-standard VU-DAB

CK5/6 D5/16B4 Dako 1:50 CCI-standard VU-DAB

CK14 LL002 Signet 1:50 CCI-mild VU-DAB

MSA HHF35 Dako 1:50 None VU-DAB

ER SP1 Ventana Neat CCI-mild VU-DAB

PR PGR636 Dako 1:100 CCI-standard VU-DAB

HER2 4B5 Ventana Neat CCI-mild VU-DAB

GCDFP-15 23A3 Dako 1:50 CCI-standard VU-DAB

Table 1 Antibodies and immu-nostaining protocols

CCI Ventana proprietary buffer,VU-DAB Ventana UltraViewdiaminobenzidine kit, HCMsmooth muscle heavy chainmyosin, MSA muscle specificactin, ER oestrogen receptor, PRprogesterone receptor, HER2Her2–neu, CK cytokeratin,GCDFP-15 gross cystic diseasefluid protein-15

Table 2 Patient demographic information, treatment, and outcome

Case 1 Case 2 Case 3 Case 4 Case 5

Age (years) 44 44 84 50 50

Clinicalpresentation

Patient palpateda new mass

Recurrent cyst requiringrepeated drainage overseveral years.Mammogram showedarea of concern

Bilateral recurrent cystsrequiring drainage.New onset mastalgiain left breast

Bilateral recurrent cystswith pain (left>right)

Recurrent leftbreast cyst

Surgery Left partialmastectomy

Left partial mastectomyand sentinel lymphnode biopsy

Left partial mastectomy Left partial mastectomy withreexcision and sentinellymph node biopsy

Left partialmastectomyand sentinellymph nodebiopsy

Radiation No 42.5 Gy in 16 fractions No No No

Systemictherapy

No No No No No

Follow-up(months)

36 17 41 7 3

Furtherprocedures

Right breast biopsyfor nodularity onclinical exam—negative formalignancy

Left breast pain withabnormalmammographicfindings. Left breastbiopsy—negative formalignancy

Left breast biopsies×2due to new nodularityand pain at site ofscar—negative formalignancy

MRI - bilateral cysts andenhancement at 6 o’clockright breast. US—hypoechoic nodular lesion.Biopsy—tubular adenoma

None

Postexcisionrecurrence

None None None None None

Status Alive Alive Alive Alive Alive

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Pathological findings

Core biopsies were performed in four patients—two wereinterpreted as malignant (high-grade apocrine DCIS andlow-grade apocrine papillary carcinoma), one as apocrine

neoplasm of uncertain malignant potential, and one asfibrocystic change with apocrine metaplasia. These all wenton to partial mastectomies with two requiring fine wirelocalisation prior to surgery. The cytology of the fine needleaspirates performed prior to excision in four of the casesshowed apocrine cells and histiocytes that were interpretedas consistent with fibrocystic change.

Macroscopic findings

All cases showed a cystic mass that ranged in size from 1.2to 4.5 cm. The cysts were received in a collapsed statewhich accounts for the discrepancy between the gross sizeand the size measured on imaging studies. The entirepapillary component of the lesion was submitted forhistological evaluation in all cases, and the encompassingcyst wall was sampled extensively. No other grossabnormalities were identified. The adjacent tissue wassampled in all cases. Fibrocystic changes were identifiedin the adjacent breast tissue.

Microscopic findings

All lesions were largely cystic with one or more papillarynodules attached to the wall of the cyst. A true papillaryarchitecture characterised by cores of sclerotic fibrovascularstroma was observed within the tumours (Fig. 3). In allcases, the papillary structures were covered by a layer ofproliferated apocrine cells (Fig. 4). The apocrine cell layervaried in complexity from a single cell layer through tomultilayered epithelium forming a pseudopapillary and/orcribriform architecture. Apocrine cells also lined the cystwall in all cases. There was no evidence of an infiltrativepattern outside the wall of the cyst. The apocrine cellsshowed a variable degree of cytological atypia but nuclear

Fig. 2 Left breast ultrasound from case 4 demonstrating a 10-cm cystcontaining a 1.6-cm echogenic nodule

Fig. 1 Mammograms (left medial lateral oblique views) of case 3 afour years prior to diagnosis revealing small mass and b at diagnosisshowing an increase in size of the mass

Fig. 3 Intracystic papillary tumour showing the prominent papillaryarchitecture of the lesion (H&E×40)

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pleomorphism was mild in three cases. One case showedlarge nuclei with prominent nucleoli (Fig. 5). Mitoses wereseen within the apocrine cells in four cases but no atypicalmitoses were detected (Fig. 6). There was no zonal necrosisbut individual cell necrosis was seen focally in all but onecase, possibly attributable to ischaemia. Two casescontained calcifications. Lymphovascular invasion wasabsent. There was no evidence of in situ or invasive diseasein the surrounding breast tissue but one case had a nearbyfocus of atypical ductal hyperplasia (ADH). Three patientsunderwent sentinel lymph node biopsies which werenegative for metastases.

Immunohistochemical features

In all five cases, the presence of myoepithelial cells wasinvestigated using a panel of immunostains (Table 1). Nomyoepithelial cells were detectable within the papillary

structures or at the periphery of the cyst (Figs. 7 and 8). Thenormal adjacent breast tissue provided good internal controlstaining. Three of the five cases were tested for oestrogenreceptor, progesterone receptor, and Her2–neu and werefound to be negative. The apocrine nature of the lesionswas confirmed by positive immunostaining for gross cysticdisease fluid protein-15 (GCDFP-15; Fig. 9).

Discussion

Encapsulated (intracystic) papillary carcinomas often pres-ent as a palpable mass in the subareolar region mostfrequently in older women. They may be associated withnipple discharge which in some instances is blood-tinged.The associated cysts can vary in size from a fewcentimetres to 10 cm. [4]. Mammography of these

Fig. 6 Mitoses present within the apocrine cells of the papillaryprocesses (H&E×200)

Fig. 5 Atypical apocrine cells lining the papillary processes in onecase (H&E×400)

Fig. 4 Papillary structures covered by apocrine cells (H&E×100)

Fig. 7 Immunostain for p63/heavy-chain myosin exhibiting absenceof myoepithelial cells within the papillary processes (×200)

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carcinomas reveals a well-circumscribed mass [5]. They areoften single, ill-defined, and lobulated and occasionallyshow microcalcifications. Ultrasonographic findings in-clude a hypoechoic lesion with posterior enhancement anda cystic portion that may show septation [6].

Originally thought to be a form of DCIS arising within acyst, EPC is now thought to be a carcinoma with“expansile” or “pushing” invasion [2, 4, 7, 8] akin to theinvasive pattern of nodular high-grade invasive ductalcarcinomas. This conclusion is based on the absence ofmyoepithelial cells within the lesion and at its periphery,and because a few cases have been described to developmetastatic spread to the regional lymph nodes [3]. Howev-er, it has been shown that in some breast proliferations themyoepithelial cells show reduced staining or complete lossof expression of some myoepithelial markers [9, 10].Alternatively, it has been argued that the myoepithelialcells could appear to be falsely absent due to attenuationsecondary to distention of the cyst [11], and indeed, somecases otherwise acceptable as EPC show small foci ofresidual myoepithelial cells in the cyst wall that do notnegate the diagnosis. Furthermore, given the observationthat absence of myoepithelial cells is known to occur insome benign “infiltrative” lesions of the breast such asmicroglandular adenosis, this cannot be used as an absoluteindicator of invasive malignancy. Other authors stillconsider EPC to be an in situ process because of thepresence of basement membrane material at the peripheryof the lesion [12]. However, one of the cases included inthat report showed micrometastases to the axillary nodeswhich makes a purely in situ lesion improbable. Neverthe-less, clinically malignant behaviour in EPC is distinctlyunusual especially in lesions that measure less than 2 cm indiameter [13]. Moreover, most cases are treated effectivelywith complete surgical excision only. Currently, it is our

practice pattern to recommend a sentinel lymph nodebiopsy at the time of wide excision but not an axillarylymph node dissection. Others recommend that EPC betreated the same as DCIS [13].

We report five patients with a pure apocrine papillaryintracystic tumour very similar to classical EPC of thebreast. These tumours are cystic and contain one or moremural nodules with a papillary architecture lined byapocrine epithelial cells that are apparently of one type.Furthermore, they lack identifiable myoepithelial cells bothwithin the papillary component and at the periphery of thecyst. Care was taken in this series of cases to ensure that themyoepithelial layer was absent by performing multipleimmunostains for these cells on many blocks from eachcase. Furthermore, the entire papillary component of thelesion was examined, and the cyst wall was sampledgenerously. Although several cytological and architecturalpatterns of EPC have been recognised [14, 15], to the bestof our knowledge, a purely apocrine variant has not beendescribed in the pathology literature. Certainly, there are nofollow-up studies of lesions of this type upon which to baselogical management decisions. There are two case reportsof apocrine carcinomas that presented as cystic lesions[16, 17]. Both of these lesions showed focal infiltrationbeyond the wall of the cyst, and one case showed apocrineDCIS in adjacent ducts. In both cases, the apocrine cellsshowed cytological features of malignancy.

In most breast proliferations, particularly in papillarylesions, the presence of apocrine cells favours a benignprocess [13]. However, there is evidence that some apocrinelesions are clonal, are associated with ADH [18], and mayprogress to malignancy [19–23]. The absence of definitecytological features of malignancy including markednuclear enlargement; marked variation in nuclear size,macronucleoli, irregular nucleoli, atypical mitotic figures,

Fig. 9 Immunostain for GCDFP-15 confirming the apocrine nature ofthe lesion (×100)

Fig. 8 Immunostain for p63 to show absence of myoepithelial cells atthe periphery of the cyst and normal adjacent lobules (×200)

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and necrosis; and the absence of DCIS in the adjacent breastargue in favour of a benign lesion. Rigid cytological criteriafor malignancy are a prerequisite for distinguishing betweenatypical apocrine adenosis and apocrine malignancy withinthe small tubular units of adenosis [20, 24], but low-gradeapocrine DCIS involving large ducts outside of adenosislesions may not show those overt cytological features ofmalignancy [25–28]. Benign apocrine cysts usually have adouble layer of apocrine cells and myoepithelial cells whilebenign papillomas have myoepithelial cells within thepapillary processes [29–31]. However, it has also beenreported that benign apocrine lesions in the breast some-times lack myoepithelial cells [32]. Therefore, this lesioncould be interpreted as intracystic apocrine papillaryhyperplasia or an intracystic apocrine papilloma.

In order to comply with the traditional terminology ofWorld Health Organization classification of breast tumours,we have chosen to adopt the terminology of “encapsulatedapocrine papillary carcinoma” for the lesion describedherein. However, we stress that the malignant potential ofthis lesion has not yet been proven, and these lesions areprobably best considered to be tumours of uncertainmalignant potential for the purposes of clinical manage-ment. Furthermore, the term tumour is used in a broad wayto indicate the uncertainty as to whether or not this lesion isa form of papillary hyperplasia or a true neoplasm. Ifneoplastic, distinction between papilloma and EPC remainsan academic debate. Although the behaviour of theapocrine variant of EPC appears to be favourable basedon this series of five cases, this study is limited by the smallsample size and the short follow-up, particularly relevant toa low-grade malignancy. Since, in the available literature,there are no reports of such lesions behaving in a malignantfashion clinically, and since none of the cases has recurredor metastasized, we prefer to regard them as of uncertainmalignant potential. This terminology is used to indicate toclinicians that this lesion should not be treated in themanner of typical invasive ductal carcinoma of the breast.In particular, the role of radiotherapy in the management ofthese lesions requires more evidence that these lesions areclinically malignant.

Conflict of interest statement We declare that we have no conflictof interest.

References

1. Fayanju OM, Ritter J, Gillanders WE et al (2007) Therapeuticmanagement of intracystic papillary carcinoma of the breast: theroles of radiation and endocrine therapy. Am J Surg 194:497–500

2. Collins LC, Carlo VP, Hwang H et al (2006) Intracystic papillarycarcinomas of the breast: a reevaluation using a panel ofmyoepithelial cell markers. Am J Surg Pathol 30:1002–1007

3. Mulligan AM, O'Malley FP (2007) Metastatic potential ofencapsulated (intracystic) papillary carcinoma of the breast: areport of 2 cases with axillary lymph node micrometastases. Int JSurg Pathol 15:143–147

4. Mulligan AM, O'Malley FP (2007) Papillary lesions of the breast:a review. Adv Anat Pathol 14:108–119

5. Wagner AE, Middleton LP, Whitman GJ (2004) Intracysticpapillary carcinoma of the breast with invasion. AJR Am JRoentgenol 183:1516

6. McCulloch GL, Evans AJ, Yeoman L et al (1997) Radiologicalfeatures of papillary carcinoma of the breast. Clin Radiol 52:865–868

7. Leal C, Costa I, Fonseca D et al (1998) Intracystic (encysted)papillary carcinoma of the breast: a clinical, pathological, andimmunohistochemical study. Hum Pathol 29:1097–1104

8. Lerwill MF (2004) Current practical applications of diagnosticimmunohistochemistry in breast pathology. Am J Surg Pathol28:1076–1091

9. Werling RW, Hwang H, Yaziji H et al (2003) Immunohistochem-ical distinction of invasive from noninvasive breast lesions: acomparative study of p63 versus calponin and smooth musclemyosin heavy chain. Am J Surg Pathol 27:82–90

10. Hilson JB, Schnitt SJ, Collins LC (2009) Phenotypic alterations inductal carcinoma in situ-associated myoepithelial cells: biologicand diagnostic implications. Am J Surg Pathol 33:227–232

11. Bhargava R, Dabbs DJ (2007) Use of immunohistochemistry indiagnosis of breast epithelial lesions. Adv Anat Pathol 14:93–107

12. Esposito NN, Dabbs DJ, Bhargava R (2009) Are encapsulatedpapillary carcinomas of the breast in situ or invasive? A basementmembrane study of 27 cases. Am J Clin Pathol 131:228–242

13. Collins LC, Schnitt SJ (2008) Papillary lesions of the breast:selected diagnostic and management issues. Histopathology52:20–29

14. Carter D (1977) Intraductal papillary tumors of the breast: a studyof 78 cases. Cancer 39:1689–1692

15. Lefkowitz M, Lefkowitz W, Wargotz ES (1994) Intraductal(intracystic) papillary carcinoma of the breast and its variants: aclinicopathological study of 77 cases. Hum Pathol 25:802–809

16. Mardi K, Sharma J, Sharma N (2004) Apocrine carcinoma of thebreast presenting as a solitary cyst: cytological and histopatho-logical study of a case. Indian J Pathol Microbiol 47:268–270

17. Angunawela P, de Silva MV, Yoheswaran K (1997) Apocrinecarcinoma of the breast masquerading as a tension cyst. CeylonMed J 42:104–105

18. Page DL, Dupont WD, Jensen RA (1996) Papillary apocrinechange of the breast: associations with atypical hyperplasia andrisk of breast cancer. Cancer Epidemiol Biomarkers Prev 5:29–32

19. Endoh Y, Tamura G, Kato N et al (2001) Apocrine adenosis of thebreast: clonal evidence of neoplasia. Histopathology 38:221–224

20. Seidman JD, Ashton M, Lefkowitz M (1996) Atypical apocrineadenosis of the breast: a clinicopathologic study of 37 patientswith 8.7-year follow-up. Cancer 77:2529–2537

21. Selim AA, El-Ayat G, Wells CA (2001) Immunohistochemicallocalization of gross cystic disease fluid protein-15, -24 and -44 inductal carcinoma in situ of the breast: relationship to the degree ofdifferentiation. Histopathology 39:198–202

22. Wells CA, El-Ayat GA (2007) Non-operative breast pathology:apocrine lesions. J Clin Pathol 60:1313–1320

23. Elayat G, Selim AG, Wells CA (2009) Cell cycle alterations andtheir relationship to proliferation in apocrine adenosis of thebreast. Histopathology 54:348–354

482 Virchows Arch (2009) 455:477–483

24. Carter DJ, Rosen PP (1991) Atypical apocrine metaplasia insclerosing lesions of the breast: a study of 51 patients. Mod Pathol4:1–5

25. O'Malley FP, Bane AL (2004) The spectrum of apocrine lesions ofthe breast. Adv Anat Pathol 11:1–9

26. Leal C, Henrique R, Monteiro P et al (2001) Apocrine ductalcarcinoma in situ of the breast: histologic classification andexpression of biologic markers. Hum Pathol 32:487–493

27. Tavassoli FA, Norris HJ (1994) Intraductal apocrine carcinoma: aclinicopathologic study of 37 cases. Mod Pathol 7:813–818

28. O'Malley FP, Page DL, Nelson EH et al (1994) Ductal carcinomain situ of the breast with apocrine cytology: definition of aborderline category. Hum Pathol 25:164–168

29. Papotti M, Eusebi V, Gugliotta P et al (1983) Immunohistochem-ical analysis of benign and malignant papillary lesions of thebreast. Am J Surg Pathol 7:451–461

30. Hill CB, Yeh IT (2005) Myoepithelial cell staining patterns ofpapillary breast lesions: from intraductal papillomas to invasivepapillary carcinomas. Am J Clin Pathol 123:36–44

31. Raju UB, Lee MW, Zarbo RJ et al (1989) Papillary neoplasia ofthe breast: immunohistochemically defined myoepithelial cells inthe diagnosis of benign and malignant papillary breast neoplasms.Mod Pathol 2:569–576

32. Cserni G (2008) Lack of myoepithelium in apocrine glands of thebreast does not necessarily imply malignancy. Histopathology52:253–255

Virchows Arch (2009) 455:477–483 483