CHAPTER 26
Tumors of the Mammary Gland
Susan E. Lana, Gerard R. Rutteman,
Stephen J. Withrow
CANINE MAMMARY TUMORS
Mammary neoplasms are among the most common
tumors of the female dog. Estimates of lifetime risk for
malignant tumors vary from 2% to more than 20%,1,2 a
risk assessed to be exceeded twofold to fivefold by that
of benign mammary tumors. Two studies of large popu-
lations of dogs have recently reported incidence infor-
mation. The first study, involving a defined population
of insured dogs in the United Kingdom, reported a stan-
dardized incidence rate for mammary tumors of 205
per 100,000 dogs per year.3 The second study surveyed
a population of more than 80,000 insured female dogs
in Sweden and found an overall incidence for any
mammary tumor of 111 per 10,000 dog years at risk.4
This study also found that the incidence increased with
age; at age 6 years, it was 1%; at age 8 years, 6%; and at
age 10 years, 13%.4 The incidence of both benign and
malignant tumors in specific populations of dogs corre-
lates with life expectancy and is strongly reduced by the
practice of ovariohysterectomy in young dogs, which is
common in the United States but not encouraged in
some European countries. The incidence is increased by
the use of injectable progestins to prevent estrus. The
risk in male dogs is 1% or less of that in female dogs.
The median age of tumor manifestation is 10 to
11 years of age, with rare occurrence in dogs younger
than 4 years old. Several spaniel breeds and, according
to some studies, the poodle and dachshund seem to be
predisposed to the condition.5-7 A recent report,
however, suggested that the incidence of malignant
tumors was different in small breed dogs compared
with large breed dogs.8 In this study, of 101 tumors
(60 small breed, 40 other), 25% of the small breed dogs
had histologically malignant tumors compared with
58% of the large breed patients.
The development of mammary tumors in the dog is
clearly hormone dependent. Compared to the risk in
intact dogs, the risk for malignant tumors in dogs
spayed before the first estrus is 0.05%; after the first
estrus, it is 8%; and it rises to 26% if the dog is spayed
after the second estrus.9 Later spaying does not reduce
the risk for malignant tumors, although the risk for
benign tumors seems to be reduced by ovariectomy
even at a later age.10 In a retrospective study of 137 dogs
with malignant mammary carcinomas, dogs spayed
within 2 years of the development of the malignant
tumor showed a survival advantage over dogs intact or
spayed 2 years or longer before mastectomy.11
A protective effect of (early) pregnancy, well-known
in humans, has not been demonstrated.9 Most likely,
the tumor-enhancing effect of ovarian steroids,
predominantly progesterone, is brought about by their
mitogenic activity in mammary cells, exerted after they
bind to their respective receptors. Normal mammary
gland tissue contains both estrogen receptors (ERs) and
progesterone receptors (PRs) receptors (as do most
benign tumors), often at increased level. In contrast,
carcinomas, devoid of remnants of normal mammary
epithelium, contain ERs and PRs in a decreased number
of cases, with rare occurrence in metastases.12-16 In a
study by Millanta and colleagues,17 85 mammary
lesions (28 dysplasias, 21 benign lesions, and 36 carci-
nomas [4 in situ, and 32 invasive]) from 47 dogs were
evaluated by means of immunohistochemistry for ER
and PR expression. Ten normal mammary tissues were
used for comparison. The researchers found that 100%
of the normal and dysplastic tissues and 95% of the
benign tissues tested positive for ERs. Of the invasive
carcinomas, 92% showed some ER staining, although
only 62% had strong nuclear staining. No significant
difference in quantitative ER expression was found
between normal, dysplastic, benign, and in situ lesions,
whereas the ER expression in invasive carcinomas was
significantly lower. In this same study, PR expression
was significantly lower in both benign and malignant
lesions compared with healthy tissue.17
In another report, 228 tumors (155 malignant,
73 benign) from 100 dogs were evaluated by immuno-
histochemistry for ER and PR expression.18 In all
tumors, one or both receptors were detected in 76% of
samples (96% of benign samples, 66% of malignant
619
620 Part IV Specific Malignancies in the Small Animal Patient
samples). In seven cases of lymph node metastasis,
both the primary tumor and the node were considered
ER and PR negative. Overall, this pattern suggests a loss
of steroid dependency for malignant mammary tumors.
Prolactin, an important hormone for the development
of mammary tissue, has been examined in tissue and
serum from canine patients with both benign and
malignant mammary tumors.19 Prolactin levels were
significantly higher in the tissues and serum from
malignant tumors than in normal mammary tissue.
It is well known that in the female dog, progesterone
or synthetic progestins such as chlormadinone acetate
(CMA) or medroxyprogesterone acetate (MPA) induce
full lobuloalveolar development of the mammary
gland, with hyperplasia of secretory and myoepithelial
elements, whereas estradiol stimulates ductal growth.
However, prolonged administration of estrogens has
not been shown to increase the incidence of mammary
tumors in dogs. Conversely, progesterone administered
to young female beagles mainly leads to the develop-
ment of benign nodules. The risk for malignant tumors
becomes higher after long-term experimental adminis-
tration of estrogens combined with progestins at
high dosage or if drugs are used that have a combined
progestagenic-estrogenic activity.20 Injectable progestins
used to prevent estrus in dogs have been shown to
increase the incidence of benign tumors but not malig-
nant tumors,10 although an increased incidence of the
latter also has been reported.21 Administration of pro-
gestins to dogs also has been shown to increase the secre-
tion of growth hormone (GH). This progestin-induced
GH gene expression was found to originate from
normal mammary gland epithelium.22 It is not known
whether the progestin-induced GH acts as an intermedi-
ate in the progestin-stimulated development of canine
mammary tumors.
Parallel to the increase in GH production induced in
the dog by progestins, a rise in the blood levels of
insulin-like growth factor I (IGF-I) and IGF-II has been
shown to occur,23 which may stimulate mammary cell
proliferation. Hormonally controlled and autonomous
expression of growth factors and their receptors also
may influence mammary tumorigenesis, making it a
highly complex process.
Many genes are involved in the normal transmission
of growth-promoting signals from the cell surface to the
nucleus (e.g., ras). The ras proteins tend to be overex-
pressed in many human tumors, but studies of canine
mammary tumors using polymerase chain reaction
(PCR) analyses have failed to reveal expression of ras
genes.24,25 Regarding oncogenes expressing for the
receptor of growth factors, one study found overexpres-
sion of messenger ribonucleic acid (mRNA) for c-erbB-2
(also called c-neu) in most canine malignant (but not
benign) mammary tumors,26 whereas another study
found that its protein was expressed more often in
benign tumors (50%) than in malignant ones (19%).27
Recently Dutra and coworkers28 reported on c-erbB-2
protein expression in 48 malignant canine mammary
tumors using the commercially available HercepTest
system, which is an immunohistochemistry-based assay
approved for use in human breast cancers. They found
that although none of the 22 benign tumors overex-
pressed c-erbB-2, 35.4% of malignant tumors did.28
Standardization of methodology is necessary to allow
proper interpretation of results and to elucidate the role
of c-erbB-2 in canine mammary neoplasia.
The p53 tumor suppressor gene is the most
frequently mutated gene in human cancer. Recent stud-
ies in canine mammary cancer found that three of 1029
and six of 4030 primary cancers contained p53 muta-
tions, with one dog carrying a germ-line mutation.29,30
In another study, 17% of 69 canine mammary carcino-
mas assayed showed a p53 gene mutation, and multi-
variate analysis indicated that this mutation conferred
an increased risk of recurrence and death from
mammary tumor.31 Alterations of a second tumor
suppressor gene, BRCA1, which is responsible for part
of hereditary human breast cancers, has been seen in
some canine mammary cancers.32 However, the extent
to which specific genetic alterations contribute to the
pathogenesis of canine mammary tumors still needs to
be resolved. Gross abnormalities in the nuclear deoxyri-
bonucleic acid (DNA) content (DNA aneuploidy), as
detected with flow cytometry, have been found in 50%
to 60% of primary cancers, occurring as either an increase
or a decrease in DNA content.3335 Also, 15% to 25% of
benign mammary tumors were aneuploid, possibly
reflecting the potential to progress to malignancy.33-35
Other factors that may play a role in the progression
of canine mammary tumors have been evaluated,
including expression of adhesion and gap junction
proteins such as E-cadherin, connexins, and paxillin.
In general, the more invasive, proliferative, and aggres-
sive a tumor was histologically, the less localized and
intense the protein expression was, indicating a shift
that favored increased cell mobility.36-38 Apoptotic path-
ways also have been explored as a contributor to
mammary carcinogenesis. In a recent study, human and
canine tumors were found to have increased patterns of
expression of antiapoptotic proteins (bcl-2, bcl-Xl) and
a significantly decreased expression of proapoptotic
proteins (Bax, caspase 8 and 3).39
Induction of cyclooxyegenase-2 (COX-2) enzymes,
thought to be involved in human breast carcinogenesis,
also has been evaluated in normal, benign, and malignant
canine mammary tissue. Dore and colleagues40 found that
COX-2 was not expressed in normal tissues but showed
increased expression in benign (24%) and malignant
(56%) tumors, indicating a possible role in tumorigene-
sis.40 An association also has been shown between COX-2
expression and tumor histologic subtype.41
 Chapter 26 Tumors of the Mammary Gland 621

Experiments in rodents and epidemiologic studies in

humans have shown that a high-fat diet and obesity
Histologic Classification of
Box 26-1
increase the risk of mammary cancer. A recent study in
Canine Mammary Tumors
pet dogs in the United States found that among spayed
dogs, the risk of developing mammary cancer was Malignant tumors
reduced if the dogs were thin at 9 to 12 months of age.42 Noninfiltrating (in situ) carcinoma
A study in Spain made a similar observation, that Complex carcinoma
obesity at 1 year of age was a risk factor for the develop- Simple carcinoma
Tubulopapillary carcinoma
ment of benign and malignant mammary tumors with-
Solid carcinoma
out consideration of ovariectomy.43 Somewhat Anaplastic carcinoma
surprisingly, the intake of homemade meals (compared Special types of carcinomas
with commercial foods) also was related to an increased Spindle cell carcinoma
risk. Nutritional factors, therefore, may play a role in Squamous cell carcinoma
canine mammary tumor development. Mucinous carcinoma
Lipid-rich carcinoma
Sarcoma
Pathology and Natural Behavior Fibrosarcoma
Based on material from veterinary practices submitted Osteosarcoma
for histologic diagnosis, 41% to 53% of mammary Other sarcomas
Carcinosarcoma
tumors that occur in the bitch are considered malig-
Carcinoma or sarcoma in benign tumor
nant.44,45 Histologic evidence of malignancy does not
invariably imply a malignant clinical course. Also, Benign tumors
marked variation in histologic appearance can occur Adenoma
within the same tumor mass. Simple adenoma
Most malignant mammary tumors are classified as Complex adenoma
epithelial tumors or carcinomas. Pure sarcomas (fibrosar- Basaloid adenoma
coma, osteosarcoma, sarcoma of another type) represent Fibroadenoma
a minority. Whether sarcomas arise from myoepithelial Low-cellularity fibroadenoma
tissue that has undergone neoplastic change or from the High-cellularity fibroadenoma
intralobular connective tissue is unclear. No evidence Benign mixed tumor
Duct papilloma
indicates that sarcomas arise from pre-existing, benign
mixed cell tumors. Some malignant tumors are From Misdorp W, Else R, Hellman E et al: Histologic classification
composed of cells that morphologically resemble the of mammary tumors of the dog and cat. In World Health
epithelial and connective tissue components (both of Organization international histological classification of tumors of
which are malignant); these tumors, which are uncom- domestic animals, series 2, vol 7, no 2, Washington, DC, 1999,
mon, are called carcinosarcomas (in some systems, malig- Armed Forces Institute of Pathology.
nant mixed tumor). Benign tumors include simple/
complex adenomas, fibroadenomas, and the relatively
common benign mixed tumor, which has an epithelial mammary neoplasia was illustrated, with 71% having
component and a mesenchymal component of cartilage at least one mammary neoplasm and 61% more than
and/or bone and/or fat, both components possibly orig- one tumor, accumulating to a total of 4755 neoplasms,
inating from a pluripotent stem cell.46,47 including 1639 carcinomas.48 Based on a histogenetic
Some histologic classification systems are based on classification system, the investigators found that of the
recognition of histologic tissue patterns thought to carcinomas, ductular carcinomas represented 19% and
identify the histogenetic origin of the tumor cells. adenocarcinomas of other histogenetic origin
However, this may have little reference to disease accounted for the rest. Only 73 carcinomas were fatal,
behavior. The revised classification established by the and ductular carcinomas were eight times more likely to
World Health Organization (WHO) (Box 26-1), in an result in fatalities than adenocarcinomas, even though
attempt to obtain a division of prognostic weight, is the difference in total (regional plus distant) metastasis
descriptive and subdivides carcinomas further into rate (46% versus 32%) was less. In this same study, true
noninfiltrating, complex, or simple carcinomas (simple carcinosarcomas were diagnosed in only five dogs, all of
carcinomas are the tubulopapillary, solid, or anaplastic which died of metastatic disease.
type). This subdivision is believed to rank the tumors by Another study of 356 female beagles determined a
increasing potential for malignancy. lifetime risk of 63% for the development of any
In a recent study covering the full life span of mammary hyperplasia or tumor, and 23% for the devel-
672 intact female beagles, the multifocal nature of opment of a malignant tumor.2 In this study the
622 Part IV Specific Malignancies in the Small Animal Patient

metastatic rate was higher, reaching 77% in 72 dogs Tumors may be associated with the nipple or, more
with carcinoma. Infiltration of the carcinoma into adja- often, the glandular tissue itself. The dog has five pairs
cent tissues was considered of greater prognostic impor- of glands, all of which can develop one or more benign
tance than the histologic subtype.2 or malignant tumors. Roughly 65% to 70% of canine
A different study applied a classification system tumors occur in glands 4 and 5, probably because of the
adopted from a prognostic human pathologic staging greater volume of mammary tissue in these glands.
system in 158 pet dogs with mammary cancer.45 In animals with benign mammary tumors, the tumor is
Carcinomas were assigned to one of four histologic small, well circumscribed, and firm on palpation.
grades: (1) lesions that were noninfiltrating (i.e., in situ Clinical signs of malignancy include rapid growth, ill-
carcinoma [grade 0]); (2) lesions that invaded the defined boundaries, fixation to the skin or underlying
surrounding stroma but without identifiable vascular or tissues, and ulceration or inflammation (Figure 26-2).
lymphatic invasion (grade I); (3) lesions that showed The presence of one or more of these signs may indicate
vascular or lymphatic invasion and/or metastasis to an increased risk of an underlying malignant growth.
regional lymph nodes (grade II); and (4) lesions that
showed pathologic evidence of distant metastasis
(grade III). The tumors were categorized further accord-
ing to the degree of nuclear differentiation (poorly
differentiated, moderately differentiated, or well differ-
entiated). Both the grade and the degree of differentia-
tion were found to be significantly related to tumor
aggressiveness.45
Another grading scheme recently was reported to have
prognostic significance by Karayannopoulou and
colleagues.49 In this study, a grade was determined for
each case by scoring three different criteria: tubule forma-
tion, nuclear pleomorphism, and mitotic counts.
Each criterion received a score ranging from 1 to 3, and
the total score was used to describe a tumor as well differ-
entiated (grade I), moderately differentiated (grade II), or
poorly differentiated (grade III). Eighty-five cases of carci-
noma were followed for 2 years after mastectomy. The Figure 26-1
authors found that patients with grade III tumors had a
Bilateral inflammatory carcinoma with vaginal edema
significantly worse survival rate than those with grade I or and edema of the leg in a dog. Vaginal cytology and
grade II tumors. They also found a 21-fold increased risk fine-needle cytology of the popliteal lymph node were
of death from the tumor with grade III lesions compared positive for cancer.
to grade I or grade II tumors.49
A specific designation is reserved for inflammatory
carcinoma. In one study, 17% of 186 malignant
mammary tumors were classified as inflammatory carci-
noma.50 Histologically, there is evidence of a poorly
differentiated carcinoma with extensive evidence of both
mononuclear and polymorphonuclear cellular infil-
trates and often edema. Dermal lymphatic invasion also
can be seen histologically. Clinically, these neoplasms
grow and metastasize extremely rapidly and invade
lymphatics in the skin, resulting in marked edema and
inflammation (Figure 26-1).51 In a study of 21 cases, all
were found to be estrogen receptor (ER) negative.52

History and Signs

Mammary tumors manifest clinically as single or (in
more than half of cases) multiple nodules within the
mammary gland, developing simultaneously or subse- Figure 26-2
quently. Multiplicity may be less common in bitches Inflammatory carcinoma in a dog, showing ulceration
with a limited duration of exposure to ovarian steroids. and nodular plaque formation.
 Chapter 26 Tumors of the Mammary Gland 623

As previously mentioned, the inflammatory carcino- benign from malignant tumors has been reported to be
mas (ICs) have a unique clinical presentation. This an insensitive method;55 however, cytologic evaluation
tumor type should be suspected if a tumor is rapidly of the mass can rule out other lesions, such as inflamma-
growing, affects multiple mammary glands and overly- tory lesions or mast cell tumors. Fine-needle aspiration
ing skin, and is characterized by firmness, warmth, for cytologic evaluation may also be beneficial in the
edema, erythema, thickening, and signs of pain. All or diagnosis of inflammatory carcinomas. If lymph node
part of one or both mammary chains may be involved. metastasis is suspected, cytology should be used to assess
Extensive lymphedema of a limb or limbs adjacent to suspect nodes. The most definitive way to obtain a diag-
this type of mammary cancer also may occur. nosis is through tissue biopsy. Practitioners must keep in
Such edema is the result of occlusion of affected mind that a presurgical distinction between a benign and
lymphatics, with accompanying retrograde growth a malignant mammary tumor does not necessarily
down the limb. It is important to differentiate this type change the extent of the operative procedure.55
of malignancy from inflammatory mastitis, although
the latter is an unusual condition in dogs. Inflammatory
carcinomas tend to be quite firm and have a diffuse
Clinical Staging
swelling, whereas mastitis tends to be more localized Accurate, precise staging is important before treatment
and usually is seen after estrus, pregnancy, or false preg- is initiated (Box 26-2). The most important require-
nancy. Systemic signs often can accompany the diagno- ments of staging are to (1) evaluate the primary tumor,
sis of IC. In one study, 94% of dogs with IC had (2) evaluate the regional lymph nodes, and (3) attempt
generalized weakness, described as lack of energy, and to identify any distant metastatic sites, including distant
decreased activity compared to only 18% of dogs with lymph nodes and the lungs. The most important
other mammary tumors.50 Pain also was seen in all features to note with the primary tumor are recent rapid
33 dogs with IC (100%), compared to only 16% of dogs growth, size, clinical evidence of invasiveness (fixation
with other mammary tumors. to skin or fascia), ulceration, and clinical evidence of
Carcinoma that metastasizes to the inguinal lymph inflammatory carcinoma. The most common sites of
nodes may enter the pudendal lymphatics and spread to distant metastasis are the lungs; sublumbar, sternal, and
the internal iliac nodes. Metastasis from the internal prescapular lymph nodes; liver; and, rarely, bone.
iliac nodes may be palpable and may cause pressure on
and compression of the colon. The other common
metastatic sites include the lungs, liver, kidneys and,
less frequently, bone.53 Staging of Canine
Box 26-2
Mammary Tumors
Diagnostic Techniques and Workup
Modified system
The diagnostic workup should include a thorough phys-
ical examination and a routine hematologic and serum TPrimary tumor
chemistry profile to assess general health. A coagulo- T1 <3 cm maximum diameter
gram may be indicated in dogs suspected of having T2 3-5 cm maximum diameter
inflammatory carcinoma because of the concurrent T3 >5 cm maximum diameter
association with disseminated intravascular coagula-
NRegional lymph nodes
tion.51,54 The first evaluation should reveal whether
N0 Histologic or cytologicNo metastasis
local or loco-regional disease is amenable to complete N1 Histologic or cytologicMetastasis present
resection. The presence of an inflammatory carcinoma
invariably is associated with an intravascular tumor, MDistant metastasis
(microscopic) or metastatic disease, and rapid local or M0 No distant metastasis detected
distant recurrence after attempted surgery. If malig- M1 Distant metastasis detected
nancy cannot be excluded, thoracic radiographs in both
the right and left lateral and ventrodorsal planes should Stages
be taken before surgery to evaluate the lungs and sternal I: T1 N0 M0
lymph node for possible metastasis. In dogs, if the II: T2 N0 M0
III: T3 N0 M0
mammary tumors involve the caudal two glands, the
IV: Any T N1 M0
sublumbar region should be evaluated for metastatic
V: Any T Any N M1
lymphadenopathy using caudal abdominal radiographs
or ultrasonography. A rectal examination may reveal Modified from Owen LN: Classification of tumors in domestic
palpable evidence of internal iliac lymphadenopathy. animals, Geneva, 1980, World Health Organization.
Fine-needle aspiration with cytology to differentiate
624 Part IV Specific Malignancies in the Small Animal Patient
Therapy
Surgery remains the treatment of choice for all dogs
with mammary gland tumors except those with inflam-
matory carcinomas or distant metastasis. The type of
surgery depends on the extent of disease.
Surgical technique
The theoretical and practical pros and cons of radical
versus local excision have been extensively debated.56
In one prospective clinical trial of 144 dogs that
compared simple mastectomy (i.e., removal of the
affected gland or glands only) to chain mastectomy
(i.e., chain resection on the affected side), no difference
in recurrence rate and survival time was noted.57
Proponents of chain mastectomy argue that it is the
most likely procedure to remove all tumor (known or
occult) and that it reduces future risk by reducing the
volume of breast tissue at risk. Some also argue for
more aggressive surgery based on the observation that
some benign lesions, namely those with atypia, are
linked with an increased risk for the development of
invasive cancer.45 These arguments may have more
weight in relatively young, intact bitches. Those opposed
to routine chain resection argue that it is too much
surgery, when more than 50% of canine breast masses
are benign; a more aggressive procedure can always be
performed later on the 40% to 50% of patients with a
malignant histology (especially if margins were incom-
plete); and chain mastectomy increases the morbidity,
time, and expense of the treatment.
The primary goal of surgery is to remove all tumor by
the simplest procedure, which should take into consid-
eration possible extension of malignant lesions through
mammary lymphatics to regional nodes. More radical
surgery for localized lesions may lead to a lower risk for
the development of new tumors in only a subset of
dogs, mentioned previously; however, it does not
inhibit the outgrowth of occult metastases of the tumor
to be treated.
A variety of procedures can be used to remove canine
breast tumors, and the choice of procedure is deter-
mined by the size of the tumor, whether it is fixed to
surrounding tissue, the number of lesions, and the
probability that a local cure can be achieved.
Lumpectomy (Nodulectomy). Lumpectomy, also
called nodulectomy, is indicated for small (less than
0.5 cm), firm, superficial, nonfixed nodules, which usually
are benign. This procedure is not to be used for known
malignant tumors. The skin is incised, and the nodule is
bluntly dissected from the breast tissue with a small rim
of normal tissue surrounding the tumor nodule.
After resection the tumor is classified as benign or
malignant, and the completeness of removal is evalu-
ated. For benign lesions, even close and incomplete
removal probably is adequate. If the lesion is small,
well circumscribed, and malignant, close but clean
margins (1 to 2 cm) are acceptable. Incomplete resec-
tion of malignant tumors warrants more aggressive
removal of the entire gland.
Mammectomy. Removal of one gland is indicated
for lesions that are centrally located within the gland
and larger than 1 cm and that show any degree of fixa-
tion to the skin or fascia. Skin and/or abdominal wall
fascia should be removed with the mass, if involved.
Based on the individual patients gland confluency,
removing glands 4 and 5 as a unit or glands 1, 2, and 3
as a unit may be easier than extensively dividing normal
mammary tissue. In other words, if the individual gland
is a distinct anatomic unit, single gland removal is
acceptable.
Regional Mastectomy. Regional mastectomy origi-
nally was proposed based on the known venous and
lymphatic drainage of the mammary tissue.58,59 In the dog,
the mammary glands have been identified, depending on
their position, as the cranial thoracic gland (gland 1),
caudal thoracic gland (gland 2), cranial abdominal
gland (gland 3), caudal abdominal gland (gland 4), and
inguinal gland (gland 5). Lymphatic drainage from the
mammary glands has been documented to the axillary,
superficial inguinal, sublumbar, and cranial sternal
nodes, depending on the gland involved.
The lymphatic drainage of canine mammary tumors
is complex. Although lymphatic drainage can occur
between all glands, a recent report indicated that major
connections exist between glands 1 and 2 and between
glands 4 and 5.59 Mammary glands 1, 2, and 3 and occa-
sionally 4 drain to axillary and cranial sternal lymph
nodes. The superficial inguinal lymph nodes provide
lymphatic drainage to mammary glands 3, 4, 5, and
occasionally 2. The superficial inguinal lymph nodes
have efferent drainage to the medial iliac lymph nodes,
which then continue to the lumbar trunks and finally to
the cisterna chyli. Based on the premise of lymphatic
drainage, tumors involving glands 1, 2, or 3 should be
removed en bloc. Similarly, tumors involving gland 4 or
5 should be removed en bloc, including the adjoining
lymph nodes, which is always possible. The axillary
lymph node is removed only if enlarged (and mobile)
or cytologically positive for malignant cells.
Unilateral or Bilateral Mastectomy. Glands 1
through 5 can be removed as a unit if multiple tumors
or several large tumors preclude rapid, wide removal by
lesser procedures. Simultaneous bilateral mastectomy
also has been proposed and can be accomplished in
dogs and cats with pendulous mammae, although
staged, single chain mastectomies are better tolerated.56
These procedures are done because they may be faster
than multiple lumpectomies or mammectomies, not
because they improve survival in the dog.
Lymph Node Removal. The axillary lymph nodes
are rarely involved with mammary cancer in the dog
 Chapter 26 Tumors of the Mammary Gland
and should not be removed prophylactically. Fixed,
adherent, and large axillary nodes can only rarely be
removed completely. The inguinal lymph node should
be removed when enlarged and cytologically positive
for cancer or whenever gland 5 is removed, because it is
intimately associated with this gland.
In summary, mammary cancer in the dog should be
removed by the simplest procedure that will remove
known cancer in the mammary gland. This does not
mean that incomplete resection or debulking surgery is
acceptable. In young, intact dogs with multiple lesions,
the risk for future multiple operations would suggest
consideration of more extensive surgery.
Chemotherapy
Although adjuvant chemotherapy often is the standard
of care for breast cancer in humans, little information
exists about its efficacy for mammary tumors in dogs.
Based on established canine mammary tumor cell lines,
doxorubicin has been shown to have antitumor activity
using in vitro clonogenic assays; however, these assays
rarely recapitulate in vivo correlates.60 In one controlled
study in a small number of dogs (n = 16), half received
cyclophosphamide and 5-fluouroucil (5-FU) postoper-
atively, and half had regional mastectomy alone.61
All dogs had stage III disease, and two in each group
had histologically confirmed regional lymph node
metastasis. When the chemotherapy-treated and control
groups were compared by means of Kaplan-Meier
analysis, statistically superior differences were seen in
both the disease-free interval (24 months versus 2 months)
and survival (24 months versus 6 months). Although
the power of this study is low, it may support the use of
adjuvant chemotherapy in certain cases.61 Additional
studies are needed to determine the optimal
chemotherapeutic agent or agents for the treatment of
canine malignant mammary tumors. Future clinical
trials should concentrate on adjuvant chemotherapy of
dogs with poor prognostic factors (e.g., large, lymph
nodepositive, invasive, high-grade tumors) after
complete surgical removal.
Radiation therapy
As with chemotherapy, no reliable information on the
value of radiation is yet available. Radiation therapy, like
surgery, is mainly limited by the extent of the tumor and
may only be considered useful in dogs with tumors that
are too extensive for surgery. Patients with malignant
tumors and complete resection do not need radiation.
The role of radiation for malignant tumors with incom-
plete margins has not been defined in dogs. Radiation
therapy (8 Gy in 2 or 3 fractions) has been tried in inop-
erable patients and patients with inflammatory carci-
noma, resulting in anecdotal reports of palliation. More
carefully designed studies are needed before the efficacy
of irradiation for canine mammary tumors can be stated.
625
Biologic response modifiers
Studies of nonspecific immunomodulation using
levamisole56 and Corynebacterium parvum with bacillus
Calmette-Gurin (BCG) combined with surgery show
little effectiveness over surgery alone.62 Based on an
early study showing a favorable effect of intravenous
BCG on survival, the WHO comparative oncology
group performed a double-blind, prospective study on
130 bitches with confirmed mammary cancer treated by
chain resection. The dogs were treated with intravenous
BCG (live Pasteur strain), C. parvum vaccine, or intra-
venous (IV) saline. No statistical differences were
reported in the 1-, 2-, and 3-year survival rates for the
three treatment groups.63 In another prospective study,
no difference in recurrence rates was seen between dogs
operated on for invasive cancer that received liposome
muramyl-tripeptide phosphatidylethanolamine (L-MTP),
a derivate from the mycobacterium cell wall that is
encapsulated in liposomes, and dogs that received
empty liposomes.64 No validated, clinically applicable
immunomodulating approach is available that can be
considered to have proven therapeutic effectiveness.
Hormonal therapy
Although early ovariohysterectomy (OHE) clearly has a
preventative role in the development of mammary
tumors in dogs, the issue of OHE for therapeutic bene-
fit remains unresolved. In one study of 154 dogs treated
with concurrent mastectomy and OHE, the mean
survival time was reported to be 8.4 months.65 This
offers no survival advantage compared to the mean
survival times of 10 and 8 months in other studies for
dogs treated by mastectomy alone.44 More recent retro-
spective studies in mammary cancer did not show any
benefit of OHE on the tumor-related66 or overall death
rate.67 One study reported improved survival in dogs if
the animal was ovariohysterectomized less than 2 years
before or at the time of mammary cancer resection,
compared to those that remained intact or were ovario-
hysterectomized more than 2 years before mammary
cancer resection.11 However, incomplete staging in this
study and the presence of favorable prognostic factors
(including tumor type) were more common in the first
group of dogs. There have been no well-designed prospec-
tive studies that clearly address the issue of OHE as an
adjunct treatment for dogs with malignant mammary
tumors.
Antiestrogens, such as tamoxifen, have been tested
both in vitro for antiproliferative activity in canine
mammary tumor cell lines60 and to a limited degree in
clinical cases.68,69 Postulated adjuvant antitumor activ-
ity by tamoxifen could not be documented in a study of
limited size in 18 dogs after mastectomy and OHE
because of frequent (10 of 18 dogs) estrogen-like signs
related to tamoxifen side effects. These side effects
include vulvar swelling, vaginal discharge, incontinence,
626 Part IV Specific Malignancies in the Small Animal Patient

Box 26-3 Summary of Canine Mammary Tumor Prognostic Factors*

Good Poor Indifferent

<3 cm in diameter >3 cm in diameter Age
Well circumscribed Invasive, ulcerated Breed (small breeds may have
more benign tumors8)
Lymph node: Negative Lymph node: Positive OHE status at time of surgery
ERs or PRs: Positive ERs: Negative Weight
Histologic subtype (carcinomawell Histologic subtype (carcinomapoorly Type of surgery (simple or radical)
differentiated, complex, differentiated, simple, solid,
tubular/papillary) anaplastic; inflammatory
carcinoma; sarcomas)

Tumor grade I Tumor grade III Number of tumors

Index of proliferation Index of proliferation Glands involved
AgNOR: Low count AgNOR: High count
Ki-67: Low Ki-67: High
PCNA: Low PCNA: High
p53 gene mutation
DNA aneuploidy

*These factors should serve as relative indicators of the prognosis; individual variation occurs.
OHE, Ovariohysterectomy; ERs, estrogen receptors; PRs, progesterone receptors; AgNOR, argyrophilic nucleolar organizer region, PCNA, proliferating
cell nuclear antigen.

urinary tract infection, stump pyometra, and signs of
estrus.69 At this time, tamoxifen therapy is not advised
in dogs.
Prognosis
Based on both univariate and multivariate studies, the
following factors have been determined to be prognos-
tic: tumor size, lymph node involvement, presence of
distant metastasis, histologic type, malignancy grade,
degree of nuclear differentiation, evidence of lymphoid
cellular reactivity in the tumor vicinity, degree of inva-
sion, intravascular growth, steroid hormone receptor
activity, S-phase fraction as a measure of proliferation,
deoxyribonucleic acid (DNA) aneuploidy, and number
of silver-staining nucleolar organizer regions (AgNORs)
(Box 26-3).* Factors that do not seem to be associated
with the prognosis are the tumor location, number of
tumors present, type of surgery (as long as histologically
adequate resection is achieved), and OHE at surgery,
although controversy exists regarding the importance of
age at diagnosis.9,57,70-74 The influence of breed accord-
ing to the patients size or weight also has been evalu-
ated. One study found that small breed was associated
with longer survival, but also that small breed dogs had
*References 13, 14, 34, 45, 57, 62, 67, and 70-72.
a higher incidence of benign tumors.8 In dogs with
malignant tumors, breed and weight have not been
shown to influence survival.74
One study found a correlation between the histologic
grade (as described previously) and the disease-free
interval after mastectomy in 158 dogs with mammary
cancer.45 Only 19% of the dogs with grade 0 (in situ or
noninvasive) carcinomas had recurrence or metastasis
within 2 years after initial mastectomy compared to
60% of dogs with grade I disease (stromal invasion) and
97% of dogs with grade II disease (invasion into vascu-
lar or lymphatic vessels). The prognosis is very good for
dogs with noninvasive carcinoma (Figure 26-3).
The degree of nuclear differentiation (i.e., poorly,
moderately, or well-differentiated tumors) also has
been shown to be an important factor in the prognosis.
The risk of developing recurrent or metastatic carci-
noma in less than 2 years after mastectomy was 90% for
dogs with poorly differentiated tumors, 68% for those
with moderately differentiated tumors, and only 24%
for those with well-differentiated carcinoma.45 A report
using a different grading scheme also showed prognos-
tic significance for nuclear differentiation; patients with
grade III tumors had a shorter survival time and an
greater likelihood of tumor-related death.49 In this
study, tumor size did not influence grade and was not
associated with survival, but lymph node metastasis
worsened the prognosis.
 Chapter 26 Tumors of the Mammary Gland
Figure 26-3
Kaplan-Meier disease-free interval curve comparing
histologic grade after mastectomy in 158 dogs with
malignant mammary tumors. Grade 0, n = 35; grade I,
n = 76; grade II, n = 47. The three stages are significantly
different; p <0.0001. (From Kurzman ID, Gilbertson SR:
Semin Vet Med Surg 1:25-32, 1986.)
Lymphoid cellular reactions in the tumor vicinity are
another factor that has been correlated with the progno-
sis. Lymphoid cellular activity may indicate morpho-
logic evidence of an antitumor immune response. In one
study, dogs with mammary cancer that did not have
evidence of lymphoid cellular activity at the time of initial
mastectomy had a significantly higher risk of develop-
ing recurrence within 2 years than those with reactivity.45
In this study, dogs with histologic grade I tumors show-
ing lymphoid cellular reactivity had a 45% recurrence
rate within 2 years, and dogs without cellular reactivity
had an 83% recurrence rate within 2 years.
Mammary sarcomas are considered to have a poor
prognosis.72,75 Most dogs with sarcomas die of the disease
within 9 to 12 months. With carcinomas, the histologic
subtype has been shown to influence survival. In one
study of 99 dogs, those with anaplastic carcinoma had
a worse postoperative survival in univariate analysis
(median survival, 2.5 months) than dogs with adenocar-
cinoma (median survival, 21 months), solid carcinoma
(median survival, 16 months), and other types of
tumors (median survival, 24 months).74 However, this
finding did not hold up in multivariate analysis.
In another report, the tumor grade was associated with
627
Figure 26-4
Kaplan-Meier disease-free interval curve comparing
tumor size after mastectomy in 54 dogs with locally
invasive, malignant mammary tumors. Dogs with
tumors smaller than 3 cm in diameter (n = 16) had
significantly longer disease-free intervals than dogs with
tumors 3 to 5 cm (n = 20) or larger than 5 cm (n = 18);
p <0.04. (From Kurzman ID, Gilbertson SR: Semin Vet
Med Surg 1:25-32, 1986.)
the histologic subtype, with simple carcinomas having a
higher percentage of grade III undifferentiated tumors
(50%) than grade I tumors (18%). Inflammatory carci-
nomas also have a poor prognosis.51,54 Most cannot be
resected surgically, and if resected, they tend to recur
within weeks to 1 month after surgery. These patients
also often have some degree of disseminated intravascu-
lar coagulation, and excessive bleeding frequently occurs
at the time of surgery. In one study, 33 dogs with IC had
a mean survival time of 25 days with palliative care.50
Tumor size is an important prognostic factor
(Figure 26-4). The WHO clinical staging system catego-
rizes dogs according to the diameter of the largest
malignant tumor (see Box 26-2). In dogs with locally
invasive disease, significant differences have been found
between T1 and T2, and T1 and T3 tumors, and in some
but not other studies between T2 and T3 tumors.67,70,74
Dogs with invasive cancer that have tumors smaller
than 3 cm in diameter have a significantly better prog-
nosis than dogs with malignant tumors 3 cm in diame-
ter or larger (Figure 26-4). In one study of a group of
dogs with invasion of lymphatic vessels or lymph node
metastasis, no significant differences were found among
T1, T2, and T3 tumors.70 In another study, dogs with a
628 Part IV Specific Malignancies in the Small Animal Patient
T3 carcinoma (over 5 cm in diameter) had a median
survival time of 40 weeks, compared to 112 weeks for
animals with smaller tumors.76 In yet another study,
dogs with tumors smaller than 3 cm in diameter survived
significantly longer (22 months) than dogs with tumors
larger than 3 cm (14 months).74
In univariate analyses, lymph node involvement
predicted poorer disease-free survival, with 80% of the
dogs with lymph node involvement having recurrence
within 6 months.45,70,73 In contrast, dogs with mammary
carcinoma (excluding sarcomas) with negative lymph
nodes usually have a recurrence rate of 30% or lower by
2 years after surgery70 (Figure 26-5). Karayannopoulou
and colleagues49 also reported that lymph node metasta-
sis had a negative impact on survival. During a 2-year
follow-up period, 24 of 28 patients (86%) with positive
lymph nodes died of disease, compared to 8 of 38 patients
(21%) that did not have lymph node metastasis.
The presence of metastatic disease at the time of diag-
nosis also has a worse prognosis. In one study, the
median postoperative survival was 5 months, compared
to 28 months for dogs without metastasis at presenta-
tion.74 In another study, the presence of ERs or PRs
(or both) above a certain threshold (10 fmol/mg
cytosolic protein) correlated with improved survival in
Figure 26-5
Kaplan-Meier disease-free interval curve comparing
lymph node metastasis after mastectomy in 45 dogs with
malignant mammary tumors. Dogs in which the lymph
nodes tested negative (n = 26) had a significantly longer
disease-free interval than those in which the lymph nodes
tested positive (n = 19); p <0.001. (From Kurzman ID,
Gilbertson SR: Semin Vet Med Surg 1:25-32, 1986.)
45 dogs with mammary cancer after surgery.13 Whether
the presence of steroid receptors is an independent prog-
nostic factor is questionable, because the presence of these
receptors has been correlated with well-differentiated
tumors, and they have been found more often in
complex than simple carcinomas.77 A study involving
84 patients looked at receptor status as a prognostic
indicator for disease-free progression (DFP). Although
univariate analysis indicated that ER+ or PR+ or both
had a favorable influence on DFP, this did not hold up
in multivariate analysis.18
In a study of 136 dogs with mammary cancer and
adequate follow-up, both the presence of DNA aneu-
ploidy and a high S-phase percentage (a measure of
the proliferation rate) were associated with reduced
survival time.72 Multivariate analyses diminished the
value of DNA ploidy status, leaving a high S-phase
fraction (SPF), sarcoma, and age as important prog-
nostic factors that increased the hazard of death from
tumor or unknown cause.72 Other immunohisto-
chemical techniques detect the presence of antigens
expressed during the cell cycle, including Ki-67 and
proliferating cell nuclear antigen (PCNA). Of these,
the Ki-67 labeling index recently was indicated to be
of prognostic value.78
Additional investigation has been done using cyto-
logic preparations instead of routine histologic samples.
In a study of 31 dogs, the Ki-67 proliferation indices
were lower for nonmalignant tumors, and high Ki-67
index values correlated with metastasis, death from
disease, and a low overall disease-free interval (DFI)
and survival rate.79 In addition, a high AgNOR count
(another proliferation marker) was implicated as a
prognosticator in canine mammary cancer.80 In one
study, multivariate analysis indicated that a mutation in
the p53 gene conferred an increased risk of tumor recur-
rence and death from mammary tumor.31 Continued
investigation into these and other molecular markers
hopefully will lead to clinically useful predictors of the
prognosis or, more important, will define potential
targets for therapeutic strategies.
FELINE MAMMARY TUMORS
Mammary tumors are the third most common tumor in
the cat, after hematopoietic neoplasms and skin
tumors.1,81-83 The incidence of mammary tumors in the cat
is less than half that seen in humans and dogs; however,
these tumors account for 17% of neoplasms in female
cats.1,82-84 Mammary tumors also have been reported in
male cats, although less often (1% to 5% of feline
mammary tumors).85,86 In contrast to humans and dogs, at
least 85% of feline mammary tumors are malignant.76,81-83
Some evidence indicates a breed-associated predilec-
tion for mammary tumors; domestic shorthair and
 Chapter 26 Tumors of the Mammary Gland
Siamese cats appear to have higher incidence
rates.82,87,88 Siamese cats may have twice the risk of any
other breed of developing mammary tumors.86
Mammary neoplasia has been reported to occur in cats
from 9 months to 23 years of age (mean age, 10 to
12 years).82-90 One study suggests that the disease occurs
at an earlier age in Siamese cats and that the incidence
in this breed reaches a plateau at 9 years of age.82 The
mean age reported for a group of 39 male cats
(12.5 years) was slightly higher than that seen in females.85
Hormonal influences probably are involved in the
pathogenesis of mammary tumors in the cat. Dorn and
coworkers1 found that cats ovariectomized at 6 months
of age had approximately a sevenfold reduced risk of
mammary cancer than intact cats. More recently, in a
case control study by Overly and colleagues,91 cats
spayed before 6 months of age had a 91% reduction in
their risk of mammary carcinoma compared to intact
cats, and cats spayed before 1 year of age had an 86%
reduction in risk. A strong association also has been
documented between previous use of drugs containing
synthetic progestins or estrogen-progestin combina-
tions and the development of benign or malignant
mammary tumors in cats; in both cases, the risk was
more than threefold over that in untreated cats.92
A benign fibroepithelial hyperplasia may be seen in
some cats recently exposed to sex steroids.
Evidence that sex steroids may interact with
mammary cells and thereby influence mammary
tumorigenesis comes from the observation that both
normal tissue and benign proliferative lesions
frequently express low levels of ERs and moderate levels
of PRs.13,93,94 A less frequent expression of ERs and PRs
in feline mammary carcinomas suggests loss of steroid
dependence during malignant progression.13,93,95
Because of this and other similarities (e.g., histopatho-
logic appearance and pattern of metastasis), feline
mammary carcinoma has been proposed as a useful
comparative model for hormone-independent human
breast carcinomas.96 To this end, recent molecular stud-
ies have evaluated HER2/neu overexpression in feline
mammary carcinomas. When amplified and overex-
pressed in human breast cancer, HER2/neu (c-erbB-2)
has been associated with clinically aggressive tumors
and an overall poorer prognosis. This overexpression is
reported to occur in 10% to 40 % of human breast carci-
nomas.97,98 Millanta and colleagues97 reported the same
overexpression in 59% of 47 cases of feline mammary
carcinoma studied and found it to be significantly asso-
ciated with a shorter overall survival. A second study
reported that the feline HER2 gene kinase domain had
92% homology to its human counterpart; it also found
HER2 overexpression in 39% of mammary carcinomas
tested.98
Other molecular targets have been investigated in
feline mammary tumors to elucidate the prognosis or
629
the pathways of tumorigenesis. Many of these targets
suggest an analogy between feline mammary carcinoma
and aggressive human breast cancer. In one study, cyclin
A, which acts as a regulatory protein in cell cycle progres-
sion, was found in 46% of tumors tested but was absent
in benign mammary tissue.99 Immunohistochemical
staining for vascular endothelial growth factor (VEGF)
also has been investigated in malignant tissues in cats,
and a higher percentage of cells that stained positive for
VEGF has been correlated with an unfavorable progno-
sis.100 E-cadherin, a cell adhesion molecule, has been
shown to be reduced or absent in 70% of feline
mammary carcinomas compared to normal tissue.101
Reports on the importance of p53 overexpression or
mutations are conflicting with respect to feline
mammary carcinomas.102,103
Pathology and Natural Behavior
Mammary tumors and dysplasias
Between 85% and 93% of feline mammary tumors are
histologically malignant. Many of the tumors, espe-
cially the large, more invasive neoplasms, adhere to the
skin and are ulcerated. Lymphatic and lymph node
invasion is common.84,87,90 In several studies, more
than 80% of cats with mammary malignancy had
metastases to one or more of the following organs at the
time of death: lymph nodes, lungs, pleura, liver,
diaphragm, adrenal glands, and kidneys.82,84,87,89,104
More than 80% of feline mammary tumors are classi-
fied histologically as adenocarcinomas.83-87 The frequency
of diagnosis of the specific types of adenocarcinomas
differs slightly among pathologists, but most agree that
tubular, papillary, solid, and cribriform carcinomas are
the most common, and some carcinomas show a combi-
nation of histologic types in one lesion. Sarcomas, squa-
mous cell carcinomas, and mucinous carcinomas are less
common malignancies. Inflammatory mammary carci-
noma recently was reported in three cats based on the
rapidly progressing clinical signs and on the associated
inflammation and dermal lymphatic invasion.105
Approximately 15% of mammary masses are benign
neoplasms or dysplasias, including simple/complex
adenomas and fibroadenomas.81,84,87,89,104 In addition,
there are three types of noninflammatory hyperplasia of
the feline mammary gland: ductular hyperplasia, lobu-
lar hyperplasia, and fibroepithelial hyperplasia.
Fibroepithelial hyperplasia
Fibroepithelial hyperplasia81 may occur in young cats
shortly after a (silent) estrus from about 6 months of
age, or during pregnancy until 2 years of age. This has
also been reported in both male and female cats treated
with exogenous progestins.94,106-110 One or (more often)
several glands may be enlarged, and sometimes
massive, two-sided enlargement is seen (Figure 26-6).
630 Part IV Specific Malignancies in the Small Animal Patient
Figure 26-6
Gross appearance of fibroepithelial hyperplasia in a
young cat.
This is thought to result from hormonal stimulation of
the glandular tissue. The mass may become erythema-
tous, ulcerated, and necrotic, leading to bleeding and
localized infection. Edema of the skin and subcutis is
common and occasionally may extend to the rear legs.
Fibroepithelial hyperplasia can also resemble acute masti-
tis. Treatment involves removal of the hormonal influence,
if possible; regression has been seen after termination of
pregnancy in some affected animals. Ovariohysterectomy
was found effective in most cases, with gradual regression
of the masses over weeks to months. If an OHE is to be
performed and the glands are still greatly enlarged, a flank
incision should be considered. In animals experiencing the
influence of long-acting, injectable progestins, removal of
the hormonal influence may be difficult, and clinical signs
may not resolve with OHE.109
History and Signs
Feline mammary cancers often are in an advanced state
of development by the time the cat is brought to the
veterinarian.88 The neoplasm may adhere to the overly-
ing skin or the underlying abdominal wall. The tumor
usually is firm and nodular. At least 25% of affected
patients have ulcerated masses. The involved nipples
may be red and swollen and may exude a tan or yellow
fluid. The tumor may involve any or all of the
mammary glands without left-right or cranial/caudal
predeliction.87,88,90,104 More than half of affected cats
have multiple gland involvement.84,85,87,88 Metastatic
lung and thorax involvement may be extensive and may
cause respiratory insufficiency as a result of a pleural
carcinomatosis with an effusion, often containing
malignant cells.
Diagnostic Techniques and Workup
Before any diagnostic or therapeutic steps are taken, the
cats health status must be fully assessed. A serum chem-
ical profile, urinalysis, and complete blood count
should be done to identify any presurgical abnormali-
ties. The number, site, and size of primary tumors
should be recorded, together with possible signs of fixa-
tion. Alterations in the size and consistency of lymph
nodes should be assessed, and any suspected node
should be aspirated or biopsied. Thoracic radiographs
should be taken in both the right and left lateral and
ventrodorsal planes to search for pulmonary, lymph
node, and pleural metastases. Mammary tumor
pulmonary metastases appear as interstitial densities.
They range from those that are faintly seen, to those that
are several centimeters in diameter, to miliary pleural
lesions than can produce significant effusion. Sternal
lymphadenopathy occasionally is seen.
Because these tumors so often are malignant, an
aggressive approach should be taken to confirm the diag-
nosis. Except for cases in which fibroepithelial hyperpla-
sia is suspected based on the history and clinical signs, a
preliminary biopsy usually is not recommended, because
80% to 85% of the masses in a mammary gland will be
malignant. However, cytology may be helpful for ruling
out nonmammary malignancies. Tissue for histopathol-
ogy is taken at the time of mastectomy.
Clinical Staging
The most important goals of staging of malignant
tumors (Box 26-4) are to (1) evaluate the primary
tumor or tumors, (2) evaluate the regional lymph
nodes, and (3) identify any distant metastatic sites.
 Chapter 26 Tumors of the Mammary Gland 631

nodes and then to sternal nodes. The caudal two glands

Staging of Feline drain to inguinal lymph nodes. In contrast to the dog, in
Box 26-4
Mammary Tumors which more conservative resections may be appropriate in
carefully selected cases, most cats require a complete
Modified system unilateral or bilateral mastectomy. Tumor fixation to skin
or abdominal fascia necessitates en bloc removal of these
TPrimary tumor structures. Complete unilateral mastectomy usually is
T1 <2 cm maximum diameter performed if the tumor (or tumors) is confined to one
T2 2-3 cm maximum diameter
side. Staged mastectomy (2 weeks apart) or simultaneous
T3 >3 cm maximum diameter
bilateral mastectomy is done when tumors are bilateral.
NRegional lymph nodes The inguinal lymph node is almost always removed with
N0 No histologic/cytologic metastasis gland 4, whereas the axillary lymph nodes are removed
N1 Histologic/cytologic metastasis only if they are enlarged and cytologically test positive for
tumor. Aggressive or prophylactic removal of axillary
MDistant metastasis nodes is unlikely to have therapeutic benefit.88,110-112
M0 No evidence of metastasis Although OHE has not been shown to reduce the
M1 Evidence of metastasis incidence of recurrence, some believe it is
warranted.82,88,113 If the mammary mass was caused by
Stages a benign condition (e.g., fibroepithelial hyperplasia),
I: T1 N0 M0
OHE often results in regression of the hyperplastic
II: T2 N0 M0
tissue (see earlier discussion).
III: T1,2 N1 M0
T3 N0,1 M0
IV: Any T Any N1 M0 Radiation therapy
Radiation therapy is not used routinely to treat feline
Modified from Owen LN: Classification of tumors in domestic mammary tumors. Currently, no evidence indicates that
animals, Geneva, 1980, World Health Organization. radiation improves the survival rate of patients with
feline mammary tumors.

The size of the primary tumor and clinical evidence of Chemotherapy

invasiveness (fixation to skin or fascia) lead to the proper
T category in the tumor-node-metastasis (TNM) system.
The regional lymph nodes should be examined carefully,
and fine-needle aspiration or surgical removal may be
necessary to determine metastasis and to help categorize
the N status. In the M category, any sign of distant metas-
tasis establishes M1 status; this includes involved distant
lymph nodes, pleural effusion proven to contain tumor
cells or radiographic signs of metastatic disease in the
lungs, or radiographic or ultrasonographic signs of
lymph node involvement in the thorax or abdomen.
Surgery
Mammary neoplasms in the cat have been treated in a
variety of ways. Surgery is the most widely used treat-
ment. It may be used alone or in combination with
chemotherapy or other modes of cancer therapy.
The success of surgery is hindered by the invasive
nature of the disease and its tendency for early metasta-
sis. Chain mastectomy (i.e., removal of all four glands
on the affected side) is the surgical method of choice
because it significantly reduces the chance of local
tumor recurrence.88,110-112 This procedure frequently is
used regardless of the size of the tumor. The cat, unlike
the dog, usually has four pairs of mammary glands.
The cranial two glands on each side have a common
lymphatic system and drain into the axillary lymph
Chemotherapy with doxorubicin (25 mg/m2 given
intravenously slowly) every 3 weeks alone or with
cyclophosphamide (50 to 100 mg/m2 given orally on
days 3, 4, 5, and 6 after doxorubicin) has induced a
short-term response in about half of cats with metasta-
tic or nonresectable local disease.114-116 Partial responses
(more than 50% regression) were noted with doxoru-
bicin alone (nine of 14 cats) and with doxorubicin with
cyclophosphamide (seven of 14 cats). The chemother-
apy protocol can be repeated every 3 to 4 weeks.
A recent retrospective study that evaluated single agent,
adjuvant doxorubicin therapy (1 mg/kg given intra-
venously every 3 weeks for five total treatments) after
surgical excision in 67 cats reported a Kaplan-Meier
median survival time of 448 days, with 59% of the
patients alive at 1 year, 37% at 2 years, and 17% at
5 years.117 The median DFI for the same study popula-
tion was 255 days. This study suggests that the use of
chemotherapy as an adjuvant holds promise for
improved outcome, but controlled, randomized trials
are needed to prove its true efficacy. In addition,
doxorubicin can be nephrotoxic in cats,118 and careful
evaluation of renal function is recommended.
Biologic response modifiers
Studies using nonspecific biologic response therapy,
such as levamisole111 and bacterial vaccines,112 have
632 Part IV Specific Malignancies in the Small Animal Patient

Figure 26-7
Kaplan-Meier survival curve comparing tumor volume after mastectomy in cats with malignant mammary
adenocarcinoma. Statistically, tumor volume is highly significant as a prognostic factor. (From MacEwen EG,
Hayes AA, Harvey HJ et al: J Am Vet Assoc 185:201-204, 1984.)

shown minimal effect on reducing the recurrence or
prolonging the survival time in cats when combined
with surgery. The use of L-MTP after mastectomy has
not shown any significant reduction in local recurrence
or survival compared to surgery alone.119 To date, no
biologic response modifier has proved efficacious in
cats with mammary cancer.
Prognosis
Little progress has been made over the past 20 years in
extending the survival time of patients with feline
mammary tumors. Because stromal invasion almost
always is present and metastases frequently are present
at the time of surgery, a guarded to poor prognosis
should always be given. With conservative surgery, two
thirds of cats in which the tumors are surgically excised
have a recurrence at the surgical site.88,110,112 Most stud-
ies state that the interval from tumor detection to the
death of the cat is 10 to 12 months.82,83,88,104,110
The most significant prognostic factors with regard to
recurrence and survival with feline malignant mammary
tumors are the tumor size,104,110,112 (Figure 26-7), extent
of surgery110 (Figure 26-8), and histologic grade.104,117,120-122
Cats with tumors larger than 3 cm in diameter reportedly
have a median survival time of 4 to 12 months.120,122
Cats with tumors 2 to 3 cm in diameter have a signifi-
cantly better median survival time of 15 to 24 months,
and cats with tumors smaller than 2 cm in diameter
have a median survival time of longer than 3 years.
Therefore both the owner and the practitioner should
realize that early diagnosis and aggressive treatment are
important prognostic factors with malignant feline
mammary tumors.
Few studies have reported on the significance of
lymph node metastasis with regard to the prognosis;
however, those that do validate the intuitive negative
effect of nodal metastasis.122,123 A recent multiinstitu-
tional trial in cats treated with surgery followed by
doxorubicin found that in cats that developed metasta-
tic disease, the location of the metastasis had prognos-
tic significance.117 In this study, the survival time for
patients with pulmonary metastasis was 331 days, and for
those with nodal metastasis, it was longer than 1500 days,
 Chapter 26 Tumors of the Mammary Gland 633

Figure 26-8
Kaplan-Meier disease-free interval curve comparing the results of conservative surgery to those of radical
mastectomy in cats with malignant mammary adenocarcinoma. Cats that undergo radical mastectomy have
a statistically significant reduced rate of local recurrence. (From MacEwen EG, Hayes AA, Harvey HJ et al: J Am
Vet Assoc 185:201-204, 1984.)

although the number of patients that developed nodal
metastasis was small.
Very few studies have been performed to evaluate the
effectiveness of the extent of local therapy in malignant
feline mammary tumors. One study showed that radical
mastectomy reduced local recurrence but did not
increase the overall survival time (see Figure 26-7).112
More recently, Novosad and colleagues117 found that
the extent of surgery had a significant effect on survival
in a subset of cats treated at a single institution; those
that underwent bilateral radical mastectomies survived
for 917 days, those that had regional mastectomies
survived for 428 days, and those that had unilateral
mastectomies survived for 348 days.
Another prognostic factor with malignant mammary
tumors is the degree of nuclear differentiation.
Well-differentiated tumors with few mitotic figures
(indicative of a low proliferation rate) have correlated
with an improved survival time.104 Unfortunately, this
tumor type is rare compared to the more undifferenti-
ated forms. In addition, a high proliferation index, as
assessed by measurement of Ki-67positive cells,
appeared to be related to reduced survival in cats
that underwent surgery for mammary carcinoma.123
Other phenotypic factors that may be indicative of the
prognosis include VEGF expression and HER2/neu
overexpression.97,100
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