Breast Cancer Research and Treatment 78: 141–148, 2003.

© 2003 Kluwer Academic Publishers. Printed in the Netherlands.

Report

Canine inflammatory mammary carcinoma: histopathology,

immunohistochemistry and clinical implications of 21 cases

Laura Peña, M. Dolores Perez-Alenza, Antonio Rodriguez-Bertos, and Ana Nieto

Department of Animal Pathology II, Veterinary Teaching Hospital, School of Veterinary Medicine, Complutense
University, Madrid, Spain

Key words: canine, histopathology, immunohistochemistry, inflammatory mammary carcinoma

Summary
Human inflammatory breast carcinoma (IBC) is the most malignant type of breast cancer with an extremely poor
prognosis. The dog is the unique animal species in which spontaneous inflammatory mammary carcinoma (IC)
has been reported, although it is not well documented. The purpose of this study was to characterize histopa-
thologically and immunohistochemically the canine IC, considering associated clinical features. Twenty-one dogs
diagnosed with IC and with known clinical and necropsy data were included in the study. Tissue samples from
necropsies underwent a histopathological review and an immunohistochemical study (Ki-67, estrogen receptor
(ER), progesterone receptor (PR), and P53 tumor suppressor protein). The histological study revealed several
types of carcinomas (solid, tubular, papillary, and adenosquamous) and three lipid-rich carcinomas. All tumors
were ER negative. Two histological patterns of neoplastic dermal infiltration were observed: tubular/papillary
and sarcomatous-like. Dermal sarcomatous-like infiltration was significantly related to previous treatments with
progestagens (p = 0.006), primary type of IC (p = 0.03), extreme local pain (p = 0.02), reduced observation of
emboli in dermal lymphatic vessels (p = 0.01), and increased expression of p53 (p = 0.001). PR expression was
significantly higher in secondary post-surgical IC (p = 0.04). The absence of PR was related to the existence of
pulmonary metastases at necropsy (p = 0.04). Canine primary IC is the most aggressive form of this disease with
distinct histopathological and immunohistochemical characteristics. Progestins and endocrine-related mechanisms
seem to be involved in canine IC development. Canine IC could serve as a spontaneous model for human IBC,
particularly in studies concerned with new therapeutics approaches.

Introduction mechanism in the invasiveness of IBC compared with

Inflammatory breast carcinoma (IBC) is a special type
of a very aggressive human mammary carcinoma in
which the clinical presentation resembles an inflam-
matory process (dermatitis or mastitis) [1]. It is con-
sidered the most malignant type of breast carcinoma
with a fulminant clinical course and extremely poor
survival rate [2–5]. The etiology of IBC is unknown.
Lately, alterations on RhoC and LIBC genes have been
identified in IBC as specifically correlated with the
aggressive and invasive inflammatory phenotype [6–8]
and increased angiogenesis [9]. Enhanced E-cadherin
expression, a transmembrane glycoprotein involved
in homotypic epithelial cells adhesion, has been also
related to IBC, suggesting a different pathogenetic
other non-IBC invasive mammary carcinomas [10].
Research on this special type of mammary cancer
remains problematic. In addition to the diagnostic dif-
ficulties, there are few published studies on IBC using
biomodels. Recently, a new human transplantable in-
flammatory carcinoma xenograft has been established
in scid/nude mice [11]. Also, models of human IBC
have been developed using a primary IBC cell line
(SUM149) [6] and human mammary epithelial cells
overexpressing the RhoC gene [7].
The dog is the unique animal species in which
spontaneous inflammatory mammary carcinoma (IC)
has been reported. It was initially described in 10
bitches which developed similar clinical and patho-
logical characteristics to those observed in humans
142 L Peña et al.
[12]. No other specific studies on canine IC have
been published since then, probably due to the rarity
of this neoplasm. Recently, in a 5-year retrospective
study including 33 cases, IC has been described as an
uncommon but distinct entity in dogs [13]. Two clin-
ical types of IC (primary and secondary) have been
observed in the dog [13] and in the woman [14–17].
Taking into account the potential use of dogs as a
natural model for studying IBC, the aim of the present
study was to characterize the canine IC histopatho-
logically and inmunohistochemically (Ki-67 prolifer-
ation index, estrogen and progesterone receptor (ER
and PR) status, expression of P53 tumor suppressor
protein). The relationship between clinical, histopath-
ological, and immunohistochemical features of canine
IC were studied in order to give light to this unique,
aggressive, and sparsely studied type of mammary
tumor.
Materials and methods
Animals
Thirty-three female dogs clinically diagnosed of IC
were retrospectively selected from a total of 436 dogs
presenting dysplasias and/or tumors of the mammary
gland at the Veterinary Teaching Hospital of Mad-
rid (VTHM) over a period of 5 years (1995–99) and
which were used for a previous study on canine IC
[13]. Due to the aggressive behavior of the disease,
dogs that were not euthanatized at diagnosis survived
a mean of 25 days (±1.7). Necropsy was conducted
in 21 cases with the consent of the owners. Only
these 21 animals out of the 33 diagnosed dogs have
been used in the present study. The diagnostic cri-
teria for IC were based on clinical features described
in dogs [12] and women [1]: rapidly growing disease
of the mammary gland and overlaying skin character-
ized by diffuse involvement of multiple glands (with
or without mammary nodules), firmness, warmth, ed-
ema, erythema, thickening, and pain. Descriptive,
reproductive, and clinical data, including radiological
examination of the thorax and special features of the
mammary region and extremities, were available from
clinical records. The mean age of the bitches was
11.4 ± 0.3 years. Five dogs were mixed-breed and 16
were pure breed. Most of them (20/21, 95.2%) were
sexually intact. All dogs had multiple mammary gland
involvement. Both mammary chains were involved
in 11 cases (52.8%). Edema of the proximal portion
of the limb causing lameness was seen in 14 dogs
(66.6%). Physical examination revealed signs of pain
which was categorized as moderate (n = 11, 52.3%)
and severe (n = 10, 47.6%). The type of inflam-
matory carcinoma was known in each case (primary,
n = 9; secondary, n = 12). All necropsies were
performed at the Veterinary Pathology Service of the
VTHM.
Histopathology
Paraffin blocks and H&E slides (fixed in 10% buff-
ered formalin) from necropsies were recovered for
this study and all available samples (mammary tu-
mors, affected skin, macroscopically altered subcu-
taneous and muscular tissues, regional lymph nodes,
and internal organs) underwent a histopathologic re-
view. Mammary tumors were diagnosed following the
WHO’s classification system of canine mammary tu-
mors [18]. The histologic criteria for the diagnosis of
lipid-rich carcinoma were adopted from human breast
cancer pathology [1]. In each tumor, the histological
malignant grade was established by scoring tubule
formation, nuclear pleomorphism, and mitotic rate
from 1 to 3 points, according to a human grading sys-
tem [19]. Other histologic features of the parenchyma
and stroma were separately evaluated in the mammary
tumors. Microscopic examination of the skin was per-
formed to study the possible neoplastic infiltration and
other histological alterations. Specific lipids staining
(Sudan III) from all formalin-fixed specimens and gly-
cogen staining (Best’s Carmine method) (2 cases in
which liquid nitrogen −90◦ C conserved frozen speci-
mens were available) were done in order to confirm
the H&E diagnosis.
Immunohistochemistry
Ki-67, ER, PR and P53 tumor suppressor protein
immunostaining were done on deparaffined represen-
tative sections of skin and mammary tumor, using the
streptavidin–biotin-complex peroxidase method after
a high temperature antigen unmasking protocol. The
primary antibodies used were: mouse monoclonal an-
tibody anti-human Ki-67 (clone MIB 1, Immunotech,
dilution 1:25, incubation 1 h at room temperature),
mouse monoclonal antibody anti-human ER (clone
CC4-5, Novocastra NCL-ER-LH2, dilution 1:40,
incubation overnight at 4◦ C), mouse monoclonal
antibody anti-human PR (clone 1A6, Novocastra
NCL-PR-123, dilution 1:25, incubated overnight at

4◦ C) and rabbit polyclonal antibody anti-human p53
(Novocastra CM1, dilution 1:200, incubation over-
night at 4◦ C). After the incubation with the mouse
monoclonal primary antibodies (Ki-67, ER, and PR),
the slides were incubated with anti-mouse biotinylated
secondary antibody (Dako E04233, dilution 1:200,
30 min at room temperature). P53 slides were sub-
sequently incubated with anti-rabbit biotinylated sec-
ondary antibody (Vector Laboratories BA1000, 1:400,
30 min at room temperature). Next, all the slides
were incubated with streptavidin conjugated with per-
oxidase (Zymed P50242, 1:400, 30 min, at room
temperature). All washes and dilutions were made
in Tris–Buffered-Saline (TBS) (pH 7.4). The slides
were developed with a chromogen solution containing
3-3 diaminobenzidine tetrachloride (Sigma Chemical
Co. D5059) and H2 O2 in TBS and counterstained in
hematoxylin (Sigma GH5-2-16). Positive and negative
control slides were used.
In each case, Ki-67 index was calculated as the
mean of the proportion of positive nuclei in 8–10
representative fields. ER and PR were considered
positive when more than 10% of positive cells were
observed in 10 selected fields. Positive PR immun-
ostaining intensity was also evaluated as low (+),
moderate (++), and intense (+++). P53 immuno-
staining was evaluated as 0 (negative, when less than
5% of cells were positive), + (low), ++ (moderate),
and +++ (intense). Evaluation of the intensity was
made by two observers simultaneously. Counting was
done with a computer-assisted image analyzer (Olym-
pus MicroimageTM image analysis, software version
4.0. for Windows).
Statistical analysis
The associations of epidemiological, clinical, patho-
logical, and immunohistochemical data were studied
using computer software (BMDP) [20]. Categorical
variables were analyzed by Pearson and Yates χ2
tests. Pearson correlation coefficients were used to
study continuous variables. Levene F -tests were used
to analyze the homogeneity of variances. If vari-
ances were equal, F -tests or pooled t-tests were
chosen to evaluate the variables. If variances were not
equal, then Welch tests or separate variance t-tests
were selected. Values of p < 0.05 were considered
significant.
Selected descriptive, clinical, and histopatho-
logical variables were analyzed. The histological type
of dermal invasion and the presence of lipid-
Canine inflammatory mammary carcinoma 143
containing cells in the mammary tumors were added
as variables after the histological examination. Im-
munohistochemical variables included: Ki-67 index,
PR (positive or negative), PR intensity (negative, low,
moderate/intense), and P53 intensity (negative/low,
moderate/intense).
Results
Histopathology
Histological diagnosis of the mammary gland tumor
causing IC was made in 20 cases after the reexami-
nation of the necropsy samples. In one animal, there
were three different malignant mammary tumors (car-
cinosarcoma, complex tubular carcinoma, and simple
tubular carcinoma) containing malignant lymphatic
emboli, and the tumor originating the IC could not be
established. In this case, the interpretation of immuno-
histochemistry was based on the immunoreactivity
found in neoplastic cells of emboli. The 20 mam-
mary neoplasms were classified as simple carcinomas
(solid, tubular, papillary, n = 15), adenosquamous
carcinomas (n = 2), and lipid-rich carcinomas (n =
3) (Figure 1). The diagnosis of lipid-rich carcinoma
(n = 3) was established when more than 80% of
the tumor cells were lipid-producing (lipid droplets
filled the cytoplasms). All the lipid-rich carcino-
mas presented tubular disposition. The positive lipid
Figure 1. Canine inflammatory carcinoma. Four views of a
lipid-rich carcinoma in different locations: (A) Mammary tumor.
H&E. (B) Infiltration of the dermis. H&E. (C) Lymph node metas-
tasis. Small aggregate of lymphocytes remain on the left. H&E. (D)
Detail of the dermal infiltration. The neoplastic cells show multiple
lipid droplets and cytological evidence of malignancy. H&E.
144 L Peña et al.

staining (Sudan III method) and negative glycogen

staining (Best’s Carmine method, frozen samples
available in 2 cases) confirmed the lipid nature of the
secretion. Multifocal groups of cells containing cyto-
plasmatic lipid-droplets were found in many non-lipid
rich tumors (14/20, 70.0%) with less than 80% of
cells with lipid droplets. Focal areas of cellular squa-
mous transformation were additionally seen in three
tumors. All mammary tumors were of a high histo-
logical malignant grade (HMG III). Tubular formation
was minimal in 5 cases (solid tumors, <10% of tu-
bule formation), moderate in 6 cases (10–75% of
tubule formation) and elevated in 9 cases (>75% of
tubule formation). Nuclear pleomorphism was moder-
ate (2 points) in 10 cases (50%) and marked (3 points)
Figure 2. Canine inflammatory carcinoma. Tubular/papillary type
in another 10 cases (50%). Multinucleated cells were of dermal infiltration. H&E.
seen in 8 tumors (40.0%). Mitotic rate was always el-
evated (3 points). Atypic mitoses were observed in 14
tumors (70.0%). Necrotic areas were absent (10/20,
50.0%), moderate (5/20, 25.0%), or abundant (5/20,
25.0%). Comedocarcinoma pattern (central necrosis)
was found in 7 cases (35.0%). Marked perivascular
fibrosis surrounding embolized lymphatic vessels was
seen in some mammary tumors (10/20, 50.0%) and
generalized desmoplastic stroma was only observed in
1 case. Hemorrhages were seen in 6 cases (30.0%).
Considering non-ulcerated areas, the presence of in-
flammatory cells (lymphocytes, plasma cells, and
macrophages) was not relevant in any case; they were
moderate in the majority of cases (17/20, 85.0%) and
very low in the others (3/20, 15.0%).
H&E slides of skin were available and reevalu-
ated in 19 cases. The epidermis was usually hyper- Figure 3. Canine inflammatory carcinoma. Sarcomatous-like type
of dermal infiltration. H&E.
plastic and hyperkeratotic and follicular keratosis was
frequently found. The tumor invaded the dermis in
82.2% of the cases (16/19) while dermal lymphatic cident with the infiltration pattern found in muscular
vessels emboli were seen in 73.7% (14/19) of the and adipose tissues of the mammary region and ex-
cases. Marked edema and evident dilatation (lymph- tremities. Muscular and adipose tissues were invaded
angiectasia) of non-embolized lymphatic vessels were histologically in 19 cases. The affected muscular tis-
seen in all cases. Two patterns of neoplastic dermal sue was degenerated (hyaline substance deposition),
infiltration were histologically observed: (A) tubu- atrophic or necrotic, showing different degrees of
lar/papillary pattern (Figure 2) with well-defined tu- interstitial edema and presenting inflammatory cells
bular or papillary structures (12/19, 63.1%) and (B) (macrophages and lymphocytes) as part of the tissue
sarcomatous-like pattern (Figure 3) characterized by repair. The replacement of muscular necrotic areas by
a diffuse infiltration formed by highly malignant normal adipose tissue was common. The urinary blad-
(anaplastic) independent cells, resembling a sarcoma der was edematous and presented metastases in 2 cases
(7/19, 36.8%). The dermal invasion pattern was (lipid-rich carcinoma resembling liposarcoma and tu-
sarcomatous-like in four tubular or papillary carcino- bular carcinoma). The latter tumor also metastatized
mas including one lipid-rich carcinoma which gave to the endometrium.
a picture similar to a liposarcoma (Figure 1). How- All cases had regional lymph node metastases;
ever, the dermal invasion pattern was always coin- some of them (n = 6) were very aggressive and

Table 1. Immunohistochemistry of 21 canine inflammatory
carcinomasa
Negative, Positive
total (%)
+ ++ +++ Total (%)
ER 21(∗ ) (100) 0 0 0 0 (0)
PR 6 (28.6) 3 6 6 15 (71.4)
P53 2 (9.5) 7 6 6 19 (90.5)
a Ki-67 index:
Mean = 34.86%; SEM = 2.28; Min =
17.36%; Max = 51%.
substituted completely the parenchyma. In 2 of the 3
lipid-rich carcinomas, the lipid-producing cells were
observed, as well, in metastatic lymph nodes but not
in pulmonary metastases (Figure 1).
Several different types of tumors in internal organs
were present in one dog: (1) an adenosquamous mam-
mary carcinoma (IC) infiltrating the skin with metas-
tases in axillary and inguinal lymph nodes, spleen, and
lungs; (2) a primary spleenic hemangiosarcoma with
metastases in the adrenal glands, peritoneum, lungs,
and myocardium; (3) an unilateral adrenocortical ad-
enoma and (4) a sebaceous gland adenoma in skin.
Another animal presented unilateral cortical adrenal
hyperplasia.
Immunohistochemistry results and statistical asso-
ciations are summarized in Tables 1 and 2 respectively.
Discussion
The term inflammatory breast carcinoma (IBC) was
initially used in a clinical sense to describe a special
type of locally advanced human mammary carcinoma
which simulated an inflammatory condition of the
skin [1, 21]. In the seventies, this cutaneous lesion
was found to be associated with an undifferentiated
breast carcinoma with massive involvement of dermal
lymphatic vessels [3]. There are few reports concern-
ing histological aspects of IBC. It is well known that
IBC is not a specific histologic subtype: infiltrating
ductal carcinomas, other carcinomas and unspecified
malignant tumors have been described as involved
with IBC [7, 22, 23]. In the previous study which
included 10 cases of canine IC [12], five different
types of adenocarcinomas (squamous, scirrhous and
solid) and one malignant mixed tumor were found.
Several types of carcinomas were also found in our
study although, singularly, 3 cases of lipid-rich car-
cinoma were diagnosed. Lipid-rich carcinoma has
Canine inflammatory mammary carcinoma 145
been included in the most recent WHO’s classifica-
tion for mammary tumors of the dog [18], although
it is not referenced in the veterinary literature. Lipid-
rich carcinoma is considered a rare type of mammary
carcinoma in humans [1] and in dogs [18]. The signif-
icance of the high proportion of lipid-rich carcinomas
found in this study is unknown, although some hor-
monal influences have been described in this type of
carcinoma in the women [24].
Histological study of the skin demonstrated embo-
lization of lymphatic dermal vessels in 14 of 19
animals (73.7%). The histological exam showed
two histological patterns of neoplastic dermal inva-
sion: one of a tubular/papillary pattern with well-
differentiated structures and one very anaplastic with
independent highly malignant cells resembling a sar-
coma (sarcomatous-like type). There are no previous
studies on dermal characteristics of IC in humans or
dogs. This lack of information can be attributed to
that human IBC specimens available for research are
minute in size (from fine needle aspiration and Tru-cut
skin biopsy) [25] or, in other cases, biopsies are taken
after chemotherapy has been instaured and the corre-
sponding cutaneous lesion disappeared. In the present
study, samples were taken at necropsy and no previ-
ous anti-neoplastic treatment was used (only palliative
treatments with anti-inflammatories and antibiotics);
thus, our results correspond to the untreated disease
in the dog. Furthermore, the possibility to perform
autopsies on humans is limited.
The tumor proliferation index measured by Ki-
67 immunostaining is considered a good prognostic
factor in canine malignant mammary tumors [26] but
in the present study, the Ki-67 index was very elevated
in all cases and had no association with clinical or
histopathological variables.
Several studies on ER and PR expression in human
IBC have shown variable results. ER-positive cases
varied from 22 to 52% and PR varied from 16 to 34%
[27–30]. In metastatic IBC, the proportion of steroid
receptors was low, with the PR being more expressed
than the ER (8.7% were ER positive and 17.4% were
PR positive) [31]. In our study, in which all dogs
had regional lymph node metastases, all cases were
ER negative while 71.4% were PR positive. Reduced
ER expression has been previously described in canine
malignant mammary tumors [32]. In our cases, PR ex-
pression was significantly associated with secondary
IC while the absence of PR was related to the existence
of pulmonary metastases at necropsy. This finding is in
accordance with previous reports of human IBC where
146 L Peña et al.
Table 2. Significant variables associated to the type of clinical presentation and histological infiltration
in canine inflammatory carcinoma

Type of clinical presentation

Primary IC Secondary IC

Type of histological infiltration (n = 19)

Tubular/papillary (n = 12) 3 (25%) 9 (75%) p < 0.05
Sarcomatous-like (n = 7) 5 (71.4%) 2 (28.6%)
PR (n = 21)
Negative (n = 6) 4 (66.7%) 2 (33.3%) p < 0.05
Positive (n = 15) 5 (33.3%) 10 (66.7%)
P53 (n = 21)
Negative/low (n = 9) 1 (11.1%) 8 (88.9%) p < 0.05
Moderate/intense (n = 12) 8 (66.7%) 4 (33.3%)

Type of histological infiltration

Tubular/papillary Sarcomatous-like

Previous treatments with progestins (n = 16)

No (n = 11) 9 (81.8%) 2 (18.2%) p < 0.01
Yes (n = 5) 0 (0%) 5 (100%)
Unknown (n = 3)
Local pain (n = 17)
Moderate (n = 8) 7 (87.5%) 1 (12.5%) p < 0.05
Extreme (n = 9) 3 (33.3%) 6 (66.6%)
Unknown (n = 2)
Emboli in dermal lymphatics (n = 19)
No (n = 5) 1 (20%) 4 (80%) p < 0.05
Yes (n = 14) 11 (78.6%) 3 (21.4%)
Pleomorphism (n = 19)
Low/moderate (n = 9) 8 (88.9%) 1 (11.1%) p < 0.05
High (n = 10) 4 (40%) 6 (60%)
Multinucleated cells (n = 19)
No (n = 11) 9 (81.8%) 2 (18.2%) p < 0.05
Yes (n = 8) 3 (37.5%) 5 (62.5%)
P53 (n = 19)
Negative/low (n = 9) 9 (100%) 0 (0%) p < 0.01
Moderate/intense (n = 10) 3 (30%) 7 (70%)

combined ER/PR status are suggested as prognostic
factors [27, 30].
The immunohistochemical expression of the p53
protein is due to mutations of the p53 tumor sup-
pressor gene which has been associated with poor
prognosis in human [33] and canine [34] malig-
nant mammary tumors. P53 overexpression intensity
was related with a worse clinical and pathological
aggressive behavior of the tumor in the present study
(primary IC).
Our statistical analysis confirm that the two clinical
presentations of IC found in the dog [13] (primary and
secondary) are different subtypes of IC with distinct
histopathological and immunohistochemical charac-
teristics. Despite the low number of cases included
in this study, justified by the low prevalence of the
disease, the significance of the statistical associations
found was very high. Further studies, including a
greater number of cases, would be desirable in order
to confirm these results.

Research on human IBC has increased in the last
decades although many problems still remain unre-
solved. Although an animal model of IBC has been
recently established in scid/nude mice [11], the dog
is the unique animal species in which spontaneous
IC has been reported. Several similarities have been
found between human and canine inflammatory mam-
mary carcinoma concerning histopathology, clinical
characteristics, and prevalence. Histological invasion
of dermal lymphatic vessels is similar in the two spe-
cies [13, 27]. In both species, the clinical features are
comparable, the two clinical presentations (primary
and secondary post-surgical) exist, and the clinical
outcome in both species is very aggressive. Canine
IC is a rare disease although its prevalence seems to
have increased in the last decades (from 4.4 to 7.6% of
all mammary tumors [12, 13]) as has occurred in the
nineties in the woman [35]. Both species are probably
under the influences of the same environmental and
nutritional carcinogens, since the dog, as a companion
animal, share many aspects of the owner’s life. The
reported prevalence of IC in the dog among all ma-
lignant mammary tumors (17.7%) [13] is higher than
that reported in women [2, 22, 27, 35, 36]. In our
opinion, canine IC can serve as a spontaneous model
for human IBC, being especially useful in studies on
new therapeutics approaches.
Acknowledgements
This work was supported in part by the research
project of the Complutense University No PR-269/98-
8178. We thank Dr Pedro Cuesta for assistance with
statistical analysis and Pedro Aranda for his technical
help.
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Address for offprints and correspondence: Dr Laura Peña, Depart-
ment of Animal Pathology II, Veterinary Medicine School, Com-
plutense University, 28040, Madrid, Spain; Tel.: +34 91 3943740;
Fax: +34 91 3943808; E-mail: laurape@vet.ucm.es