Virchows Arch (2006) 448: 2934

DOI 10.1007/s00428-005-0084-2
ORIGINAL ARTI CLE
Sofia Asioli
.
Gianluca Marucci
.
Guido Ficarra
.
Mark Stephens
.
Maria P. Foschini
.
Ian O. Ellis
.
Vincenzo Eusebi
Polymorphous adenocarcinoma of the breast. Report of three
cases
Received: 24 May 2005 / Accepted: 28 August 2005 / Published online: 12 October 2005
# Springer-Verlag 2005
Abstract We report three cases of polymorphous adeno-
carcinoma (PLA) of the breast in 37-, 55- and 74-year-old
women, respectively. The patients have no evidence of
previous malignancy. The tumours consist of monotonous
cells showing a wide spectrum of growth patterns: solid
nests, trabeculae, tubules, cribriform structures, strands and
fascicles reminiscent of polymorphous low-grade adeno-
carcinoma of salivary glands. To our knowledge, PLA has
never been reported in the breast; therefore, this tumour
should be added to the list of neoplastic lesions of the
breasts that have the same features as those of the salivary
glands.
Keywords Polymorphous carcinoma
.
Breast
.
Salivary
glands
Introduction
Polymorphous low-grade adenocarcinoma (PLGA) of minor
salivary glands is a term given by Evans and Batsakis [8] to a
clinicopathological entity of an intraoral malignant tumour,
which is also named as terminal duct carcinoma of the oral
cavity [13] or as lobular carcinoma of intraoral minor sal-
ivary gland origin [12]. These latter authors emphasized
similarities between tumours they have described and in-
vasive lobular carcinomas (ILCs) of the breast.
PLGA is virtually exclusive of minor salivary glands of
the oral cavity [1, 3]; in rare occasions, it has been reported
in the parotid [19] and, in even rarer occasions, in other
sites such as the lung [17], skin [24], vulva and vagina [27]
and lacrimal glands [22]. The purpose of the present paper
is to describe three cases of tumours in the breast with
morphology similar to that of PLGA of the salivary glands.
To the best of our knowledge, tumours with these features
and in such site have not been reported in the literature.
Case report
Patient 1
In 1994, a 37-year-old woman presented with a mass that
measured 1.5 cm and was located in the left breast.
The patient had no evidence of previous oropharyngeal
primary tumour. She underwent quadrantectomy with ax-
illary lymph node dissection (13 lymph nodes) followed by
radiotherapy. On gross examination, the nodule was sur-
rounded by fibrofatty tissue, appeared tan and firm and
displayed indistinct borders.
The patient developed liver metastases in early 1997 and
died with widespread metastases later in the same year.
Patient 2
A 55-year-old woman presented with a 3.5-cm-diameter
firm nodule located in the internal superior quadrant of the
S. Asioli
.
G. Marucci
.
M. P. Foschini
.
V. Eusebi
Section of Pathology, Department of Oncology,
University of Bologna, Bellaria Hospital,
Bologna, Italy
G. Ficarra
Department of Pathology,
University of Modena and Reggio Emilia,
Modena, Italy
M. Stephens
Department of Histopathology,
University Hospital of North Staffordshire,
Stafford, UK
I. O. Ellis
Department of Histopathology,
Nottingham City Hospital, University of Nottingham,
Nottingham, UK
V. Eusebi (*)
Anatomia Patologica, Ospedale Bellaria,
Universit di Bologna,
Via Altura No. 3,
40139 Bologna, Italy
e-mail: vincenzo.eusebi@unibo.it
Tel.: +39-51-6225523
Fax: +39-51-6225759
right breast, which was found to be mammographically
positive for carcinoma in November 2004. Fine-needle
biopsy showed atypical epithelial cells without myoepi-
thelial cell layers that were considered suspicious of car-
cinoma. The patient underwent quadrantectomy with
axillary lymph node dissection (20 lymph nodes) followed
by radiotherapy.
When last contacted, the patient was well 6 months after
surgery.
Patient 3
In April 2005, a 74-year-old patient presented with a firm
nodule in the upper internal quadrant of the left breast.
Fine-needle aspiration led to a positive smear for carcino-
ma. The patient was treated with simple mastectomy
together with axillary dissection (11 lymph nodes). The
nodule measured 4 cm in its greatest axis, was hard and
grey white and had infiltrative margins. There has been no
significant follow-up to date.
Materials and methods
Two cases were retrieved from V.E.'s consult files. Case 3
was encountered among routine cases.
Tissues were fixed in buffered formalin and routinely
processed with paraffin. Slides were stained with haema-
toxylineosin; for immunohistochemistry, the ABC meth-
od was employed. Source, dilution and antigen retrieval of
the antibodies used are listed in Table 1.
Fig. 1 Case 1: The tumour shows a central core composed of solid
nests, while at the periphery, neoplastic cells invade in an Indian-file
pattern
Table 1 Antibodies used
SMA Smooth muscle actin, AR
androgen receptor, ER estrogen
receptor, PR progesterone
receptor, EMA epithelial mem-
brane antigen, AnR antigen
retrieval submitting sections at
enzymatic digestion for 30 min
in protease, AnR* antigen re-
trieval (submitting sections at
high pressure for 6 min at 100C
in citrate buffer)
Antibody Clone Source Dilution, AnR
Keratin 7 OV-TL 12/30 Dako 1:100, AnR
Keratin 14 LL002 Biogenex 1:100, AnR*
SMA 1A4 Dako 1:100, AnR not performed
P63 4A4 Neomarkers 1:200, AnR*
ER 1D5 Dako 1:50, AnR*
PR PgR636 Dako 1:50, AnR*
AR AR 441 Neomarkers 1:100, AnR*
E-cadherin HECD-1 Zymed 1:1,000, AnR*
EMA E 29 Dako 1:600, AnR not performed
c-Kit Polyclonal Dako 1:70, AnR*
Chromogranin LK2H10 Biogenex 1:400, AnR*
GFAP 6F2 Dako 1:1,200, AnR*
Bcl-2 M0887 Dako 1:20, AnR*
Fig. 2 a Case 1: Solid nests as observed in the centre of the tumour.
Neoplastic cells show round, monotonous nuclei. b Case 2: Solid
nests also characterize the tumour centre of this case
30
Histology and immunohistochemistry
Patients are described together because their histology and
immunohistochemistry are very similar. Microscopically,
neoplasms are nonencapsulated and exhibit cells that in-
vade surrounding breast tissues (Fig. 1).
Neoplastic cells show a wide spectrum of growth pat-
terns consisting of solid nests and large areas that are
mostly located in the centre of the tumours (Fig. 2a and b),
while at periphery trabeculae, occasional tubules and
alveolar structures are mostly represented. In some areas,
the neoplastic cells show the single-file pattern typical of
ILCs (Fig. 3a). Combinations and transitions among all
these patterns are frequent. Occasionally entrapped pre-
existing ducts, mostly located at the periphery of the tu-
mour, are evident in case 2.
Tumour cells are composed of elements showing
moderately variable round to ovoid nuclei with dispersed
vesicular chromatin, inconspicuous to small nucleoli and
prominent nuclear membrane (Fig. 3b). Mitoses average
10/10, 10/10 and 12/10 high-power fields (HPF; 400). No
tumour necrosis is seen. The stroma within the tumours is
collagenous; in case 3, abundant basal lamina is present
among the neoplastic cells (Fig. 4). Cytology (i.e. vesicular
nuclei) shows the same features as those of the invasive
counterpart. All cases are scored as grade 2 [5]. Neither
vascular nor nerve invasion is present. No metastases are
found in regional lymph nodes in all cases. In situ duct
carcinoma of intermediate differentiation [15] is observed
at the edge of the invasive lesion in case 3.
The three tumours show similar immunohistochemical
features, with minor variations. Keratin 7 strongly and
diffusely stains several areas of both lesions, while it
appears absent mostly at the periphery of both neoplasms,
where resemblance with ILC is more evident (Fig. 5).
Keratin 14 is absent in cases 1 and 3, while it occasionally
stains cells of case 2. Smooth muscle actin is consistently
absent in all cases, as is P63 in cases 1 and 3. The same
Fig. 4 Case 3: a Solid nests and sheets as seen at low power.
b Basal lamina-like material is observed among neoplastic cells
Fig. 5 Case 1: Keratin 7 stains residual mammary glands, but
neoplastic cells are consistently negative
Fig. 3 Case 1: a Neoplastic cells showing typical Indian-file
pattern. Round, monotonous nuclei are displayed by neoplastic cells.
b Cells of a nest showing round, monotonous nuclei
31
antibody stains the nuclei of several neoplastic cellular
nests, while it is absent in other areas in case 2 (Fig. 6). E-
cadherin stains most of the cells from all cases. The stain
does not outline the cell membrane, as is usually seen in
duct carcinoma, but shows interruption of staining, here
named as fragmented E-cadherin stain (Fig. 7). Epithelial
membrane antigen (EMA) is negative in the three tumours,
as are estrogen receptor (ER) and progesterone receptor
(PR). Androgen receptors, c-kit and chromogranin are
consistently negative in the two cases stained (cases 2 and
3). On the contrary, Blc-2 strongly stains the two cases
tested (cases 2 and 3) (Fig. 8). Glial fibrillary acidic protein
(GFAP) stains only small areas in case 3 (Table 2).
Discussion
We describe three cases of breast carcinoma with features
of polymorphous adenocarcinoma (PLA) similar to those
referred to as PLGA of the salivary glands. In recent years,
most of the tumours seen in salivary glands have also been
reported in the breast [11]. These include, in addition to
the well-delineated adenoid cystic carcinoma (ACC) [16],
mucoepidermoid [4], acinic cell [2] and syringoid [11, 25]
carcinomas. Lesions also shared by the two organs are duct
carcinoma [11, 13], mixed salivary gland tumours [18]
(including carcinoma ex-pleomorphic adenoma) [14] and
adenomyoepithelioma [6] (not to mention pure myoepi-
thelial cell carcinomas) [10]. All these tumours of the
breast are morphologically similar to those of the salivary
glands, although clinical behaviour can differ, being more
aggressive in the salivary gland as a general rule [11].
The three present cases displayed a very polymorphous
structure consisting of central areas showing solid nests,
surrounded at the periphery by alveolar and cribriform
structures as well as trabeculae and Indian-file-arranged
cells. Neoplastic elements had moderate variability of
nuclei that appeared round to ovoid, with sparse vesicular
Fig. 6 Case 2: P63 stains several nuclei of this neoplastic area
Fig. 7 Case 2: E-cadherin stains only segments of the cytoplasmic
membrane (fragmented E-cadherin)
Fig. 8 Case 3: Most of the neoplastic elements are consistently
positive for Bcl-2
Table 2 Immunohistochemical results
Antisera Case 1 Case 2 Case 3
Keratin 7
Keratin 14
SMA
P63
ER
PR
AR ND
E-cadherin + +Fragmented +Fragmented
EMA
c-Kit ND
Chromogranin ND
GFAP ND
Bcl-2 ND + +
SMA Smooth muscle actin, AR androgen receptor, ER estrogen
receptor, PR progesterone receptor, EMA epithelial membrane
antigen, ND not done
32
chromatin. Mitoses ranged from 10 to 12 per 10 HPF, and
necrotic areas were absent. Bcl-2 was strongly positive in
the two cases tested, and GFAP showed areas of positive
elements in one case. All these features were consistent
with the features of PLGA as described in minor salivary
glands [1, 8].
The present tumours in the salivary glands have to be
distinguished from ACCs. The fact that they show only one
type of cell and are devoid of actin-positive elements in
both cases, as well as of c-kit in cases 2 and 3, renders these
tumours different from ACC, which, on the contrary and by
definition, shows two types of cells and actin-positive
elements [16].
ILC was simulated in the present cases by the Indian-file
pattern shown in some peripheral areas. The neoplastic
cells from the three cases were E-cadherin-positive, and
EMA, ER and PR were, on the contrary, distinctly neg-
ative, with all features being different from those seen in
ILC [7, 26]. Androgen receptors were consistently negative
in the two cases stained (cases 2 and 3)a finding that was
not common in ILCs, which were positive in nearly 90% of
the cases [21].
No evidence of neuroendocrine differentiation was pres-
ent both at structural and immunohistochemical levels
[20].
Admittedly, cases 2 and 3 are recent patients, but case 1
had a very aggressive clinical course, with the patient dying
of widespread disease 3 years after diagnosis. All three
cases were scored as grade 2, were of large sizes and had
invasive margins at the moment of diagnosis. No ER and
PR were present. Therefore, it seems that, in view of the
present data, the biological behaviour and morphological
features of the three tumours are more in consonance with
those of high-grade carcinomas. In this respect, it seems
that the term low grade, as used for the PLGA of the
salivary glands, is not appropriate for the present breast
tumours.
In the salivary glands, no fewer than 13 of 40 PLGA
cases reported by Evans and Luna [9] had local recur-
rences; six cases presented with lymph node metastases
and three cases had distant metastases. These data are in
consonance with other reports of PLGA [23] in which it
appears that, even in salivary glands, it remains an ag-
gressive lesion and, consequently, the term low grade does
not seem appropriate anymore. In the skin, three of six
cases of adenocarcinoma with features very similar to those
of the PLGA of the salivary glands recurred (two cases) or
metastasized (one case) [24]. Aggressive clinical behaviour
led these same authors [24] to name their lesion as poly-
morphous carcinoma of the sweat glandsa name that can
also be adopted in carcinoma of the breast for the same
reason. At variance with the present cases, the PLGA of the
salivary glands frequently shows neurotropism [1]. This
might be due to the limited number of the present cases or
due to different anatomic sites of origin, as the same phe-
nomenon is seen in ACCs occurring in the breast [16].
In conclusion, the purpose of the present paper was to
report on three cases of PLA of the breast, the last of
salivary-gland-like tumours that has not yet been reported
in this site. We propose that the three cases presented in this
report fill this gap.
Acknowledgements The work was financed by grant no.
2002064975 (Cofin 2002) of the Ministry of University and
Research and by the University of Bologna (60%). Dr. G. Collina
is thanked for providing us access to case 3.
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