Virchows Arch (2009) 455:477–483
DOI 10.1007/s00428-009-0834-7
ORIGINAL ARTICLE
Encapsulated apocrine papillary carcinoma
of the breast—a tumour of uncertain malignant
potential: 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 apocrine
papillary tumour are reported. All presented as cystic
masses in the breast of women aged 44–84 years. Imaging
studies showed a complex cyst often with one or more
mural nodules. The key histological features are similar to
those of classical encapsulated papillary carcinoma in that
myoepithelial cells were absent within the papillary
structures and at the periphery of the cyst. All were pure
apocrine in type and showed variable degrees of cytological
atypia and mitotic activity. All lacked evidence of malig-
nancy in the breast tissue outside of the lesion. Sentinel
lymph node biopsies performed in three of the cases were
negative for metastases, and all have behaved in a benign
fashion.
Keywords Breast neoplasms . Intracystic . Apocrine .
Papillary carcinoma
M. Seal : S. Chia
The 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, Canada
e-mail: mhayes@bccancer.bc.ca
C. Wilson
The Department of Medical Imaging,
British Columbia Cancer Agency,
Vancouver, Canada
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 a
variant of ductal carcinoma in situ (DCIS) characterised by
papillary carcinoma within a cystically dilated duct, many
authors 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 consider
a determinant for invasion. Furthermore, there have been
case reports of intracystic papillary tumours metastatic to
axillary lymph nodes and distant sites [1–3].
We present five cases of encapsulated apocrine papillary
carcinoma of the breast and evaluate the clinical outcome of
these patients. The objectives of this study are to describe the
clinical, radiological, and pathological findings of these rare
tumours and to discuss their malignant potential. Our goal is
to aid clinicians and pathologists to make treatment decisions
for patients who present with this diagnostic challenge.
Materials and methods
The clinical records, radiographical images, and pathology
slides from five patients with suspected EPC of apocrine type
seen during 1995–2009 at our centre were reviewed. Full
ethics approval was obtained before commencing study.
Hematoxylin and Eosin (H&E) stained slides were
available in all cases, and blocks were obtained for
immunostaining of myoepithelial cells using a Ventana
Benchmark XT autostainer. The antibodies used and
staining protocols are summarised in Table 1.
478 Virchows Arch (2009) 455:477–483

Table 1 Antibodies and immu-

nostaining protocols 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
CCI Ventana proprietary buffer,
VU-DAB Ventana UltraView CK5/6 D5/16B4 Dako 1:50 CCI-standard VU-DAB
diaminobenzidine kit, HCM CK14 LL002 Signet 1:50 CCI-mild VU-DAB
smooth muscle heavy chain MSA HHF35 Dako 1:50 None VU-DAB
myosin, MSA muscle specific ER SP1 Ventana Neat CCI-mild VU-DAB
actin, ER oestrogen receptor, PR
progesterone receptor, HER2 PR PGR636 Dako 1:100 CCI-standard VU-DAB
Her2–neu, CK cytokeratin, HER2 4B5 Ventana Neat CCI-mild VU-DAB
GCDFP-15 gross cystic disease GCDFP-15 23A3 Dako 1:50 CCI-standard VU-DAB
fluid protein-15

Results Breast imaging

Clinical data
The clinical details are summarised in Table 2. All patients
underwent partial mastectomy, and three had sentinel
lymph node procedures. One patient received radiotherapy
to the breast. None received systemic therapy. Although
four patients had further biopsies, all were negative for
malignancy, and no patient had recurrence. The length of
follow-up in each case is given in Table 2.
Mammograms were obtained in all cases. Four of the five
patients showed soft tissue masses ranging in size from 3 to
12 cm (Fig. 1). Ultrasound examination showed a complex
cyst with a mural nodule or intracystic papillary lesion in
four patients. These nodules measured between 8 and
16 mm (Fig. 2). One case showed pleomorphic calcifica-
tions within the mass located in the cyst. One patient had
multiple mural nodules with increased vascularity seen on
Doppler ultrasound within them.

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
Clinical Patient palpated Recurrent cyst requiring Bilateral recurrent cysts Bilateral recurrent cysts Recurrent left
presentation a new mass repeated drainage over requiring drainage. with pain (left>right) breast cyst
several years. New onset mastalgia
Mammogram showed in left breast
area of concern
Surgery Left partial Left partial mastectomy Left partial mastectomy Left partial mastectomy with Left partial
mastectomy and sentinel lymph reexcision and sentinel mastectomy
node biopsy lymph node biopsy and sentinel
lymph node
biopsy
Radiation No 42.5 Gy in 16 fractions No No No
Systemic No No No No No
therapy
Follow-up 36 17 41 7 3
(months)
Further Right breast biopsy Left breast pain with Left breast biopsies×2 MRI - bilateral cysts and None
procedures for nodularity on abnormal due to new nodularity enhancement at 6 o’clock
clinical exam— mammographic and pain at site of right breast. US—
negative for findings. Left breast scar—negative for hypoechoic nodular lesion.
malignancy biopsy—negative for malignancy Biopsy—tubular adenoma
malignancy
Postexcision None None None None None
recurrence
Status Alive Alive Alive Alive Alive
Virchows Arch (2009) 455:477–483
Fig. 1 Mammograms (left medial lateral oblique views) of case 3 a
four years prior to diagnosis revealing small mass and b at diagnosis
showing an increase in size of the mass
Pathological findings
Core biopsies were performed in four patients—two were
interpreted as malignant (high-grade apocrine DCIS and
low-grade apocrine papillary carcinoma), one as apocrine
Fig. 2 Left breast ultrasound from case 4 demonstrating a 10-cm cyst
containing a 1.6-cm echogenic nodule
479
neoplasm of uncertain malignant potential, and one as
fibrocystic change with apocrine metaplasia. These all went
on to partial mastectomies with two requiring fine wire
localisation prior to surgery. The cytology of the fine needle
aspirates performed prior to excision in four of the cases
showed apocrine cells and histiocytes that were interpreted
as consistent with fibrocystic change.
Macroscopic findings
All cases showed a cystic mass that ranged in size from 1.2
to 4.5 cm. The cysts were received in a collapsed state
which accounts for the discrepancy between the gross size
and the size measured on imaging studies. The entire
papillary component of the lesion was submitted for
histological evaluation in all cases, and the encompassing
cyst wall was sampled extensively. No other gross
abnormalities were identified. The adjacent tissue was
sampled in all cases. Fibrocystic changes were identified
in the adjacent breast tissue.
Microscopic findings
All lesions were largely cystic with one or more papillary
nodules attached to the wall of the cyst. A true papillary
architecture characterised by cores of sclerotic fibrovascular
stroma was observed within the tumours (Fig. 3). In all
cases, the papillary structures were covered by a layer of
proliferated apocrine cells (Fig. 4). The apocrine cell layer
varied in complexity from a single cell layer through to
multilayered epithelium forming a pseudopapillary and/or
cribriform architecture. Apocrine cells also lined the cyst
wall in all cases. There was no evidence of an infiltrative
pattern outside the wall of the cyst. The apocrine cells
showed a variable degree of cytological atypia but nuclear
Fig. 3 Intracystic papillary tumour showing the prominent papillary
architecture of the lesion (H&E×40)
480
Fig. 4 Papillary structures covered by apocrine cells (H&E×100)
pleomorphism was mild in three cases. One case showed
large nuclei with prominent nucleoli (Fig. 5). Mitoses were
seen within the apocrine cells in four cases but no atypical
mitoses were detected (Fig. 6). There was no zonal necrosis
but individual cell necrosis was seen focally in all but one
case, possibly attributable to ischaemia. Two cases
contained calcifications. Lymphovascular invasion was
absent. There was no evidence of in situ or invasive disease
in the surrounding breast tissue but one case had a nearby
focus of atypical ductal hyperplasia (ADH). Three patients
underwent sentinel lymph node biopsies which were
negative for metastases.
Immunohistochemical features
In all five cases, the presence of myoepithelial cells was
investigated using a panel of immunostains (Table 1). No
myoepithelial cells were detectable within the papillary
Fig. 5 Atypical apocrine cells lining the papillary processes in one
case (H&E×400)
Virchows Arch (2009) 455:477–483
Fig. 6 Mitoses present within the apocrine cells of the papillary
processes (H&E×200)
structures or at the periphery of the cyst (Figs. 7 and 8). The
normal adjacent breast tissue provided good internal control
staining. Three of the five cases were tested for oestrogen
receptor, progesterone receptor, and Her2–neu and were
found to be negative. The apocrine nature of the lesions
was confirmed by positive immunostaining for gross cystic
disease fluid protein-15 (GCDFP-15; Fig. 9).
Discussion
Encapsulated (intracystic) papillary carcinomas often pres-
ent as a palpable mass in the subareolar region most
frequently in older women. They may be associated with
nipple discharge which in some instances is blood-tinged.
The associated cysts can vary in size from a few
centimetres to 10 cm. [4]. Mammography of these
Fig. 7 Immunostain for p63/heavy-chain myosin exhibiting absence
of myoepithelial cells within the papillary processes (×200)
Virchows Arch (2009) 455:477–483
Fig. 8 Immunostain for p63 to show absence of myoepithelial cells at
the periphery of the cyst and normal adjacent lobules (×200)
carcinomas reveals a well-circumscribed mass [5]. They are
often single, ill-defined, and lobulated and occasionally
show microcalcifications. Ultrasonographic findings in-
clude a hypoechoic lesion with posterior enhancement and
a cystic portion that may show septation [6].
Originally thought to be a form of DCIS arising within a
cyst, EPC is now thought to be a carcinoma with
“expansile” or “pushing” invasion [2, 4, 7, 8] akin to the
invasive pattern of nodular high-grade invasive ductal
carcinomas. This conclusion is based on the absence of
myoepithelial cells within the lesion and at its periphery,
and because a few cases have been described to develop
metastatic spread to the regional lymph nodes [3]. Howev-
er, it has been shown that in some breast proliferations the
myoepithelial cells show reduced staining or complete loss
of expression of some myoepithelial markers [9, 10].
Alternatively, it has been argued that the myoepithelial
cells could appear to be falsely absent due to attenuation
secondary to distention of the cyst [11], and indeed, some
cases otherwise acceptable as EPC show small foci of
residual myoepithelial cells in the cyst wall that do not
negate the diagnosis. Furthermore, given the observation
that absence of myoepithelial cells is known to occur in
some benign “infiltrative” lesions of the breast such as
microglandular adenosis, this cannot be used as an absolute
indicator of invasive malignancy. Other authors still
consider EPC to be an in situ process because of the
presence of basement membrane material at the periphery
of the lesion [12]. However, one of the cases included in
that report showed micrometastases to the axillary nodes
which makes a purely in situ lesion improbable. Neverthe-
less, clinically malignant behaviour in EPC is distinctly
unusual especially in lesions that measure less than 2 cm in
diameter [13]. Moreover, most cases are treated effectively
with complete surgical excision only. Currently, it is our
481
practice pattern to recommend a sentinel lymph node
biopsy at the time of wide excision but not an axillary
lymph node dissection. Others recommend that EPC be
treated the same as DCIS [13].
We report five patients with a pure apocrine papillary
intracystic tumour very similar to classical EPC of the
breast. These tumours are cystic and contain one or more
mural nodules with a papillary architecture lined by
apocrine epithelial cells that are apparently of one type.
Furthermore, they lack identifiable myoepithelial cells both
within the papillary component and at the periphery of the
cyst. Care was taken in this series of cases to ensure that the
myoepithelial layer was absent by performing multiple
immunostains for these cells on many blocks from each
case. Furthermore, the entire papillary component of the
lesion was examined, and the cyst wall was sampled
generously. Although several cytological and architectural
patterns of EPC have been recognised [14, 15], to the best
of our knowledge, a purely apocrine variant has not been
described in the pathology literature. Certainly, there are no
follow-up studies of lesions of this type upon which to base
logical management decisions. There are two case reports
of apocrine carcinomas that presented as cystic lesions
[16, 17]. Both of these lesions showed focal infiltration
beyond the wall of the cyst, and one case showed apocrine
DCIS in adjacent ducts. In both cases, the apocrine cells
showed cytological features of malignancy.
In most breast proliferations, particularly in papillary
lesions, the presence of apocrine cells favours a benign
process [13]. However, there is evidence that some apocrine
lesions are clonal, are associated with ADH [18], and may
progress to malignancy [19–23]. The absence of definite
cytological features of malignancy including marked
nuclear enlargement; marked variation in nuclear size,
macronucleoli, irregular nucleoli, atypical mitotic figures,
Fig. 9 Immunostain for GCDFP-15 confirming the apocrine nature of
the lesion (×100)
482
and necrosis; and the absence of DCIS in the adjacent breast
argue in favour of a benign lesion. Rigid cytological criteria
for malignancy are a prerequisite for distinguishing between
atypical apocrine adenosis and apocrine malignancy within
the small tubular units of adenosis [20, 24], but low-grade
apocrine DCIS involving large ducts outside of adenosis
lesions may not show those overt cytological features of
malignancy [25–28]. Benign apocrine cysts usually have a
double layer of apocrine cells and myoepithelial cells while
benign papillomas have myoepithelial cells within the
papillary processes [29–31]. However, it has also been
reported that benign apocrine lesions in the breast some-
times lack myoepithelial cells [32]. Therefore, this lesion
could be interpreted as intracystic apocrine papillary
hyperplasia or an intracystic apocrine papilloma.
In order to comply with the traditional terminology of
World Health Organization classification of breast tumours,
we have chosen to adopt the terminology of “encapsulated
apocrine papillary carcinoma” for the lesion described
herein. However, we stress that the malignant potential of
this lesion has not yet been proven, and these lesions are
probably best considered to be tumours of uncertain
malignant potential for the purposes of clinical manage-
ment. Furthermore, the term tumour is used in a broad way
to indicate the uncertainty as to whether or not this lesion is
a form of papillary hyperplasia or a true neoplasm. If
neoplastic, distinction between papilloma and EPC remains
an academic debate. Although the behaviour of the
apocrine variant of EPC appears to be favourable based
on this series of five cases, this study is limited by the small
sample size and the short follow-up, particularly relevant to
a low-grade malignancy. Since, in the available literature,
there are no reports of such lesions behaving in a malignant
fashion clinically, and since none of the cases has recurred
or metastasized, we prefer to regard them as of uncertain
malignant potential. This terminology is used to indicate to
clinicians that this lesion should not be treated in the
manner of typical invasive ductal carcinoma of the breast.
In particular, the role of radiotherapy in the management of
these lesions requires more evidence that these lesions are
clinically malignant.
Conflict of interest statement We declare that we have no conflict
of interest.
References
1. Fayanju OM, Ritter J, Gillanders WE et al (2007) Therapeutic
management of intracystic papillary carcinoma of the breast: the
roles of radiation and endocrine therapy. Am J Surg 194:497–500
Virchows Arch (2009) 455:477–483
2. Collins LC, Carlo VP, Hwang H et al (2006) Intracystic papillary
carcinomas of the breast: a reevaluation using a panel of
myoepithelial cell markers. Am J Surg Pathol 30:1002–1007
3. Mulligan AM, O'Malley FP (2007) Metastatic potential of
encapsulated (intracystic) papillary carcinoma of the breast: a
report of 2 cases with axillary lymph node micrometastases. Int J
Surg 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) Intracystic
papillary carcinoma of the breast with invasion. AJR Am J
Roentgenol 183:1516
6. McCulloch GL, Evans AJ, Yeoman L et al (1997) Radiological
features 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, and
immunohistochemical study. Hum Pathol 29:1097–1104
8. Lerwill MF (2004) Current practical applications of diagnostic
immunohistochemistry in breast pathology. Am J Surg Pathol
28:1076–1091
9. Werling RW, Hwang H, Yaziji H et al (2003) Immunohistochem-
ical distinction of invasive from noninvasive breast lesions: a
comparative study of p63 versus calponin and smooth muscle
myosin heavy chain. Am J Surg Pathol 27:82–90
10. Hilson JB, Schnitt SJ, Collins LC (2009) Phenotypic alterations in
ductal carcinoma in situ-associated myoepithelial cells: biologic
and diagnostic implications. Am J Surg Pathol 33:227–232
11. Bhargava R, Dabbs DJ (2007) Use of immunohistochemistry in
diagnosis of breast epithelial lesions. Adv Anat Pathol 14:93–107
12. Esposito NN, Dabbs DJ, Bhargava R (2009) Are encapsulated
papillary carcinomas of the breast in situ or invasive? A basement
membrane 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. Histopathology
52:20–29
14. Carter D (1977) Intraductal papillary tumors of the breast: a study
of 78 cases. Cancer 39:1689–1692
15. Lefkowitz M, Lefkowitz W, Wargotz ES (1994) Intraductal
(intracystic) papillary carcinoma of the breast and its variants: a
clinicopathological study of 77 cases. Hum Pathol 25:802–809
16. Mardi K, Sharma J, Sharma N (2004) Apocrine carcinoma of the
breast 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) Apocrine
carcinoma of the breast masquerading as a tension cyst. Ceylon
Med J 42:104–105
18. Page DL, Dupont WD, Jensen RA (1996) Papillary apocrine
change of the breast: associations with atypical hyperplasia and
risk of breast cancer. Cancer Epidemiol Biomarkers Prev 5:29–
32
19. Endoh Y, Tamura G, Kato N et al (2001) Apocrine adenosis of the
breast: clonal evidence of neoplasia. Histopathology 38:221–224
20. Seidman JD, Ashton M, Lefkowitz M (1996) Atypical apocrine
adenosis of the breast: a clinicopathologic study of 37 patients
with 8.7-year follow-up. Cancer 77:2529–2537
21. Selim AA, El-Ayat G, Wells CA (2001) Immunohistochemical
localization of gross cystic disease fluid protein-15, -24 and -44 in
ductal carcinoma in situ of the breast: relationship to the degree of
differentiation. 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 and
their relationship to proliferation in apocrine adenosis of the
breast. Histopathology 54:348–354
Virchows Arch (2009) 455:477–483
24. Carter DJ, Rosen PP (1991) Atypical apocrine metaplasia in
sclerosing lesions of the breast: a study of 51 patients. Mod Pathol
4:1–5
25. O'Malley FP, Bane AL (2004) The spectrum of apocrine lesions of
the breast. Adv Anat Pathol 11:1–9
26. Leal C, Henrique R, Monteiro P et al (2001) Apocrine ductal
carcinoma in situ of the breast: histologic classification and
expression of biologic markers. Hum Pathol 32:487–493
27. Tavassoli FA, Norris HJ (1994) Intraductal apocrine carcinoma: a
clinicopathologic study of 37 cases. Mod Pathol 7:813–818
28. O'Malley FP, Page DL, Nelson EH et al (1994) Ductal carcinoma
in situ of the breast with apocrine cytology: definition of a
borderline category. Hum Pathol 25:164–168
483
29. Papotti M, Eusebi V, Gugliotta P et al (1983) Immunohistochem-
ical analysis of benign and malignant papillary lesions of the
breast. Am J Surg Pathol 7:451–461
30. Hill CB, Yeh IT (2005) Myoepithelial cell staining patterns of
papillary breast lesions: from intraductal papillomas to invasive
papillary carcinomas. Am J Clin Pathol 123:36–44
31. Raju UB, Lee MW, Zarbo RJ et al (1989) Papillary neoplasia of
the breast: immunohistochemically defined myoepithelial cells in
the diagnosis of benign and malignant papillary breast neoplasms.
Mod Pathol 2:569–576
32. Cserni G (2008) Lack of myoepithelium in apocrine glands of the
breast does not necessarily imply malignancy. Histopathology
52:253–255