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.
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.
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 %.
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