Max's House
Feline Mammary Tumors
E. GREGORY MacEWEN, V.M .D. Diplomate, American College of Veterinary Internal Medicine (Internal Medicine and Oncology; Professor of Medicine and Oncology, Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison; Affiliate Professor, Department of Animal Health Biomedical Sciences; Member, Wisconsin Comprehensive Cancer Center, School of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
STEPHEN J. WITHROW, D.V.M.
Diplomate, American College of Veterinary Surgeons and American College of Veterinary Internal Medicine (Oncology); Professor of Surgery and Oncology; Chief, Clinical Oncology, Comparative Oncology Unit, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado.
When a cat with a mammary mass is presented, a malignancy must be considered. At
least 80% of feline mammary tumors are malignant. Mammary tumors are known to be at least
the third most frequently occurring tumor in the cat, following hematopoietic neoplasms
and skin tumors. The incidence of mammary tumors in the cat is less than half that of
humans and dogs. However, this tumor accounts for 17% of neoplasms in female cats.
Although there is no proven breed-associated predilection for mammary tumors, some
investigators have suggested that domestic short-haired and Siamese cats have higher
incidence rates than other cats. Siamese cats may have twice the risk of any other breed
of developing mammary tumors.
Mammary neoplasia has been reported to occur in cats from 9 months to 23 years of age,
with a mean age of occurrence of 10 to 12 years. One study suggests that the disease
occurs at an earlier age in Siamese cats and the incidence reaches a plateau at about 9
years of age. The majority of affected cats are intact females; however, the disease is
occasionally seen in oophorectornized females and rarely in male cats.
Hormonal influences may be involved in the pathogenesis of mammary tumors in the cat.
Although the association between ovariohysterectorny and incidence is not as strong as in
the dog, most studies show that intact cats are more likely to develop mammary tumors than
oophorectornized cats. Studies have been done to determine the role of progesterone,
testosterone, and estrogen in causing feline mammary tumors. Low levels of progesterone
receptors have been found in the cytoplasm of some feline mammary tumors. Several reports
have also documented a strong association between the prior use of progesteronelike drugs
and the development of benign or malignant mammary masses in cats. Dihydrotestosterone
receptors have not been found in mammary tumors in cats. Only 10% of the feline tumors
assayed were positive for estrogen receptors; a much higher percentage of positive tests
is seen in dogs and humans.
Pathology and Natural Behavior
Mammory Tumors Between 80 and 85% of the feline mammary tumors will
be malignant. Many of the tumors, especially the large, more invasive neoplasms, adhere to
the skin and are ulcerated. Lymphatic and lymph node invasion is frequently present and
visible at necropsy. In several studies, more than 80% of the cats with a mammary
malignancy had metastases to one or more of the following organs at the time of
euthanasia: lymph nodes, lungs, pleura, liver, diaphragm, adrenal glands, and kidneys.
More than 80% of the feline mammary tumors are histologically classified as
adenocarcinomas. The frequency of diagnosis of the specific types of adenocarcinomas
differs slightly among pathologists, but most agree that tubular, papillary, and solid
carcinomas are the most common. The majority of adenocarcinomas have a combination of
tissue types in each tumor. Sarcomas, mucinous carcinomas, duct papillomas, adenosquamous
carcinomas, and adenomas are rarely seen. The benign mammary gland dysplasias are
infrequently reported by the pathologist, but they are an important part of a differential
diagnosis.
Mammary Hyperplasia There are two basic types of noninflammatory
hyperplasia of the feline mammary gland: lobular hyperplasia and fibroepithelial
hyperplasia.
Lobular Hyperplasia. Lobular hyperplasia occurs as palpable masses in one or more
glands. has been reported in cats from 1 to 14 years of age and most were 8 years. Most
cats were intact females. The most common type of lobular hyperplasia involves one or more
enlarged lobules with a cystic or dilated ductal component.
Fibroepithelial Hyperplasia. (Fibroepithelial hyperplasia) will usually occur in
young, cycling, or pregnant female cats and has even been seen in litters prior to their
first estrus. Old, unspayed females and males given megestrol acetate have developed this
condition. Most affected cats exhibit hyperplasia I or 2 weeks after their first estrus.
The tremendously enlarged glands may appear erythematous and some of the skin may be
necrotic. Edema of the skin, subcutis, and both rear legs is common. This condition can be
easily confused with an acute mastitis.
These conditions are thought to be associated with hormonal stimulation of the glandular
tissue. Diuretics, corticosteroids, and testosterone have been advocated but the results
are variable. Necrosis and ulceration may be associated with bleeding and localized
infection. Systemic infection and pulmonary embolism have been reported.
If an ovariohysterectorny is to be performed and the glands are still greatly enlarged,
then a flank incision should be used. In time, the glands will regress and the
ovariohysterectorny should prevent recurrence.
History and Signs
Feline mammary tumors are often presented to the veterinarian 5 months after they are
initially noted. Thus, the tumors are usually in an advanced state of development when
they are handled clinically. The neoplasm may adhere to the overlying skin but rarely
adheres to the underlying abdominal wall. The tumor is usually firm and nodular. At least
one quarter of affected patients have ulcerated masses. The involved nipples may be red
and swollen and may exudate a tan or yellow fluid. The tumor can involve any or all
mammary glands and is noted equally in the left and right sides. More than half of the
affected cats have multiple gland involvement. Metastatic lung and thorax involvement may
be extensive and may cause respiratory insufficiency because of a pleural carcinomatosis
with an effusion, often containing malignant cells.
Diagnostic Techniques and Workup
Before any diagnostic or therapeutic steps are taken, the health status of the cat must be
fully assessed. A serum chemical profile, urinalysis, and complete blood count should be
done to identify any presurgical abnormalities. Thoracic radiographs in both the right and
left lateral and ventrodorsal planes should be made to search for pulmonary, lymph node,
and pleural metastases. Mammary tumor pulmonary metastases appear radiographically 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 is occasionally seen. Changes due to aging in the lungs
and Pleura, as well as inactive inflammatory lesions, may simulate metastatic disease.
Treatment should not be withheld because of equivocal radiographic findings.
Because of the high frequency of malignancy, an aggressive approach should be taken to
confirm the diagnosis. A preliminary biopsy is usually not recommended because 80 to 85%
of the masses in a mammary gland will be malignant. However, cytology may be helpful to
rule out possible skin or subcutaneous nonmammary malignancies. Tissue for histopathology
is taken at the time of mastectomy. If pleural fluid is removed from a cat with a mammary
gland lesion, cytology should be done on the fluid to search for malignant cells.
Clinical Staging The most important features of staging are to (a)
evaluate the primary tumor and regional lymph nodes and (b) identify any metastatic sites.
The most important features to note are the number of tumors, size (very important),
location, and clinical evidence of invasiveness (fixation to skin or fascia). Regional
lymph nodes should be examined carefully and fine-needle aspiration or surgical removal
may be necessary to determine metastasis.
Therapy Mammary neoplasms in the cat have been treated in a variety
of ways. Surgery is the most widely used treatment. It may be used alone or in
combination with chemotherapy or other modes of cancer therapy.
Surgery The success of surgery is hindered by the invasive
nature of the disease and its tendency for early metastasis. Radical mastectomy (i.e.,
removal of all glands on the affected side) is the surgical method of choice because it
significantly reduces the chance of local tumor recurrence. This procedure is frequently
utilized, regardless of the size of the tumor.
The surgeon's knowledge of the anatomy of the area is critical for local control of the
tumor. The cat, unlike the dog, usually has four pairs of mammary glands. The two cranial
glands on each side have a common lymphatic system and drain into the axillary lymph nodes
and then to sternal nodes. The two caudal glands tend to drain to inguinal lymph nodes.
Several surgical principles are observed when performing a mastectomy on feline mammary
tumor patients. As opposed to the dog, in which more conservative resections may be
appropriate in carefully selected cases, most cats require a complete unilateral or
bilateral mastectomy. Tumor fixation to the skin or abdominal fascia necessitates en bloc
removal of these structures. Complete unilateral mastectomy is usually performed if the
tumor or tumors are confined to one side. Staged mastectomy (2 weeks apart) or
simultaneous bilateral mastectomy is done when the tumors are bilateral. The inguinal
lymph node is virtually always removed with gland , while the axillary lymph nodes are
removed only if enlarged and cytologically positive for tumor. Aggressive or prophylactic
removal of axillary nodes, whether positive or negative, probably has little therapeutic
benefit.
Although ovariohysterectorny has been shown not to decrease the incidence of recurrence,
some believe that it is warranted because of the occasionally seen coexisting ovarian and
uterine disease. If the mammary mass is due to a benign condition such as fibroepithelial
hyperplasia, ovariohysterectorny often results in regression of the hyperplastic tissue.
This condition often resolves spontaneously within a few weeks of diagnosis; in some cases
without performing an ovariohysterectorny.
Radiation Therapy Radiation therapy is not used routinely to
treat feline mammary tumors. Presently, there are no major claims that radiation increases
the survival rate of feline mammary tumor patients.
Chemotherapy Combination chemotherapy using doxorubicin
(25-30 Mg/M2 IV slowly) and cyclophosphamide (50-100 Mg/M2 per os days 3, 4, 5, and 6
following doxorubicin) has been shown to induce short-term responses in about half of the
cats with metastatic or nonresectable local disease. In one study, 7 of 14 (50%) had a
partial response (> 50% regression). The median survival time for those cats responding
was 5 months versus 2.5 months for the 7 cats that did not respond to doxorubicin and
cyclophosphamide. The chemotherapy protocol can be repeated every 3 to 4 weeks. We have
found that the major side effect with this protocol has been profound anorexia and mild
myelosuppression. Reducing the dose of doxorubicin to 20 to 25 Mg/M2 or I mg/kg or
substituting mitoxantrone (5 Mg/M2 q 3 weeks) may limit toxicity to an acceptable level.
In addition, it has been reported that doxorubicin can be nephrotoxic to the cat, although
this is considered uncommon. Prospective studies using combined adjuvant chemotherapy and
mastectomy in the cat have yet to be performed.
Biologic Response Modifiers Studies using nonspecific
biologic response therapy such as levamisole. and bacterial vaccines have shown minimal
effects on reducing recurrence or prolonging the survival time in cats when combined with
surgery. Studies using killed C. parvum or liposome-encapsulated muramyl tripeptide (LMTP)
after mastectomy failed to show any significant reduction in local recurrence, compared to
surgery alone. To date, we have no effective biologic response modifier available that has
been shown to be efficacious in the cat with mammary cancer.
Prognosis
In the last 20 years, little progress has been made in extending the survival time of
feline mammary tumor patients. Because stromal invasion is almost always present and
metastases are frequently present at the time of surgery, a guarded-to-poor prognosis
should always be given. With conservative surgery, 66% of the cats that have had their
tumors surgically excised have a recurrence at the surgical site. Most studies
state that the time from tumor detection to the death of the cat is 10 to 12 months
The most significant prognostic factors affecting recurrence and survival for feline
malignant mammary tumors are tumor size, extent of surgery, and histologic grading. Tumor
size is the single most important prognostic factor for malignant feline mammary tumors.
Cats with a tumor size of greater than 3 cm in diameter will have a median survival time
of 4 to 6 months. Cats with a tumor size of 2 to 3 cm in diameter will have a
significantly better survival time with a median of about 2 years, and cats with less than
a 2 cm diameter tumor will have a median survival time of over 3 years. Thus, early
diagnosis and treatment is a very important prognostic factor for malignant feline mammary
tumors.
Few studies have reported the significance of lymph node metastasis in prognosis. In one
study, 22 (49%) of 45 tumor-bearing cats had metastasis to the regional lymph node(s).
Lymph nodes were clinically palpable in only 10 (21%) of these cats. This provides further
rationale to perform a radical mastectomy, including regional (inguinal) lymph node
removal, in all cats. Because of its location, the axillary lymph node should only be
removed if enlarged or cytologically positive for tumor cells.
Very few studies have been performed to evaluate the effectiveness of the extent of local
therapy in malignant feline mammary tumors. One study did show that a radical mastectomy
would reduce the development of local recurrence but did not increase the overall survival
time. The final prognostic factor for malignant mammary tumors is the degree of nuclear
differentiation. Well-differentiated tumors with few mitotic figures have been shown to
have increased survival times but, unfortunately, are rare compared to the more
undifferentiated forms.
COMPARATIVE ASPECTS
Breast cancer is the most common malignant neoplasm in women. In the United States 1 out
of every 9 women is likely to develop the disease, and 1 out of every 4 women with cancer
will have breast cancer.
The etiology of breast cancer is unknown, although there is a familial tendency, with
daughters showing a higher incidence if their mothers had breast cancer. Another important
factor is hormone status. Early pregnancy and early oophorectomy lower the incidence,
whereas late menopause and early menarche are associated with an increased incidence.
Other factors that may play a role are fat intake, obesity, body size, radiation exposure,
and socioeconomic influences.
Pathologically, the majority of breast cancers are infiltrating duct cell adenocarcinomas
with varying degrees of fibrous tissue reaction. Overt metastasis occurs by local
infiltration to the skin, opposite breast, and lymph nodes and by blood to the bones,
lungs, liver, and brain. Bone metastases are present in more than 50% of patients with
disseminated disease.
Hormonal status plays an important role in the biologic behavior and treatment of breast
cancer. Estrogen receptors (ERS) are present in more than 60% of the tumors, progesterone
receptors (PRS) in more than 30%, and androgen receptors (ARS) in more than 20%.
Receptor-positive tumors have a better prognosis with surgery and respond to hormonal
therapies, such as oophorectomy and antiestrogens (tamoxifen).
The management of breast cancer provides a major challenge. Treatment will usually involve
a combination of mastectomy, lumpectomy, or radiation therapy to the primary site, to the
axilla, or both. Hormonal therapy (tamoxifen) will usually follow surgery in ER-positive
tumors. Chemotherapy is usually used in patients with more advanced disease (positive
lymph nodes, invasive carcinomas), and the useful agents include doxorubicin,
mitoxantrone, alkylating agents, 5-fluorouracil, and methotrexate. -
The prognosis for breast cancer treatment depends on the histologic tumor type, tumor
size, invasiveness, lymph node status, and hormonal receptor status. The survival time for
local and regional treatment of breast cancer, both of which employ partial or total
breast removal, is 57% for clinically negative nodes and 38% for clinically positive nodes
at 10 years. The benefits of adjuvant chemotherapy for node-negative women with low ER
levels, and of tamoxifen therapy for women with high ER levels, are statistically very
clear. However, the clinical magnitude of these differences is small. Adjuvant
chemotherapy/ hormonal therapy has reduced the relapse rate from 29 % to 23 %.