Mammary Tumors in Dogs and Cats
The frequency of mammary neoplasia in different species varies tremendously. The dog is by far the most frequently affected domestic species, with a prevalence ~3 times that in women; ~50% of all tumors in the bitch are mammary tumors. Mammary tumors are rare in cows, mares, goats, ewes, and sows. There are differences in both biologic behavior and histology of mammary tumors in dogs and cats. Approximately 45% of mammary tumors are malignant in dogs, whereas ~90% are malignant in cats, and dogs have a much higher number of complex and mixed tumors than do cats.
The cause of mammary tumors is unknown in any species except mice, in which an oncornavirus is causative in certain inbred strains. Hormones play an important role in the hyperplasia and neoplasia of mammary tissue, but the exact mechanism is unknown. Estrogen or progesterone receptors (or both) have been reported on mammary tumor cells in animals; these may influence the pathogenesis of hormone-induced mammary neoplasia as well as the response to hormone therapy.
Genetic and nutritional effects on mammary neoplasia have been identified in mice and some people but are still not as well understood in dogs or cats. In people, BRCA1 and BRCA2 are the most important genes significantly associated with mammary tumors. In dogs, one single nucleotide polymorphism (SNP) in exon 9 of BRCA1 and one SNP in exon 24 of BRCA2 were found to be significantly associated with canine mammary tumors. It has been demonstrated that the consumption of red meat, obesity at 1 year of age, and obesity a year before diagnosis are associated with an increased risk of mammary gland tumors in intact or ovariohysterectomized dogs.
Obesity is thought to mediate breast cancer risk in postmenopausal women by increasing circulating free estrogen levels as well as through increased local estrogen production by aromatases. It is possible that obesity increases risk of mammary tumors through similar mechanisms in dogs.
From a practical view, all mammary tumors should be regarded as potentially malignant regardless of the size or number of glands involved. Spread of mammary carcinomas in both dogs and cats is primarily to regional lymph nodes and lungs. In dogs, 5%–10% of mammary carcinomas may produce skeletal metastases, primarily in the axial skeleton, but also in long bones.
The frequency of mammary neoplasia in different species varies tremendously. The dog is by far the most frequently affected domestic species, with a prevalence ~3 times that in women. Mammary tumors in dogs are most frequent in intact bitches; ~50% of all tumors in the bitch are mammary tumors. Mammary tumors are extremely rare in male dogs. Mammary tumors are also rare in cows, mares, goats, ewes, and sows.
Ovariectomy before the first estrus reduces the risk of mammary neoplasia to 0.5% of the risk in intact bitches; ovariectomy after one estrus reduces the risk to 8% of that in intact bitches. Bitches neutered after maturity have generally been considered to have the same risk as intact bitches. However, a recent systematic review of the literature based on Cochrane guidelines found that the association between the age at spaying and the risk of mammary neoplasia was weak. In addition, any potential benefit in reduced risk of mammary neoplasia may be overcome by the increase in overall cancer risks (eg, lymphoma, hemangiosarcoma, osteosarcoma) associated with early-age ovariectomy (when performed on a patient less than 2 years of age) in certain breeds of dogs (eg, Golden Retrievers, Viszlas, Rottweilers). Questions also remain regarding the impact of ovariohysterectomy at the time of tumor excision and the timing of such surgery relative to survival. In one study, dogs spayed <2 years before tumor excision lived 45% longer than either intact dogs or those spayed >2 years before tumor excision.
The two posterior mammary glands are involved more often than the three anterior glands. Grossly, tumors appear as single or multiple nodules (1–25 cm) in one or more glands. The cut surface is usually lobulated, gray-tan, and firm, often with fluid-filled cysts. Mixed mammary tumors may contain grossly recognizable bone or cartilage on the cut surface.
More than 50% of canine mammary tumors are benign mixed tumors; a smaller percentage of malignant mixed tumors are seen. In the latter, epithelial or mesenchymal components, either singly or in combination, may produce metastases. Histologically, canine mammary gland tumors have been classified by the World Health Organization as carcinomas (with six types and additional subtypes), sarcomas (four types), carcinosarcomas (mixed mammary tumors), or benign adenomas. This classification scheme is based on the extent of the tumor, involvement of lymph nodes, and presence of metastatic lesions (TNM system); it includes unclassified tumors and apparently benign dysplasias. In addition to tumor size and the status and timing of neutering, special stains (including those for the KIT receptor and AgNOR) may have prognostic value.
Mammary tumors in cats are most common in older (average 11 years), intact females. Cats spayed before 6 months or 12 months of age have a 91% or an 86% reduction, respectively, in the risk of mammary carcinoma development compared to intact cats. Parity does not affect feline mammary carcinoma development. Unlike in dogs, in cats the two anterior or thoracic glands are more frequently involved than the posterior glands.
There are also differences in both biologic behavior and histology of mammary tumors in dogs and cats. Approximately 90% of mammary tumors are malignant in cats, and cats have fewer complex and mixed tumors than dogs. Most feline mammary tumors are adenocarcinomas, with tubular or papillary types more common than solid or mucoid types. Mixed mammary tumors and sarcomas are less commonly diagnosed than carcinomas. Benign tumors of the feline mammary gland are relatively infrequent. The TNM clinical staging system is used for mammary tumors in cats as well as in dogs.
A distinct entity called feline mammary hypertrophy has been noted in cats. It affects primarily young, actively cycling, or pregnant cats. It also has been seen in neutered cats, including older males given exogenous progestational drugs (megestrol acetate). The disorder is marked clinically by the rapid growth of one or more mammary glands.
A mammary tumor is usually suspected on detection of a mass during physical examination. The length of time the mass has been present is usually unknown, but the rate of growth may be helpful in determining prognosis. Palpation of the regional lymph nodes can help determine the extent of spread. Thoracic radiographs, preferably three views (a ventral-dorsal and two laterals), should be taken to detect pulmonary metastases.
Even though the gold standard for diagnosis of mammary tumors in dogs and cats is histopathology, fine-needle aspirates are simple, cost-effective, easy to use, relatively noninvasive, and provide quick results. Using the Robinson’s grading system to evaluate hypercellularity, variable cellular size and shape (pleomorphism, anisocytosis, macrocytosis), variable nuclear size and shape (anisokaryosis, macrokaryosis), increased nuclear-to-cytoplasmic ratio; large, prominent or multiple nucleoli, nuclear molding; chromatin clearing, chromatin clumping; presence of abnormal multinucleated cells, and mitotic figures, FNA results interpreted to be malignant were found to strongly agree with histopathologic results (66.7% agreement for grade 1, 84.6% for grade 2, and 100% for grade 3).
B-mode and Doppler ultrasonography of neoplastic mammary tissue have only moderate sensitivity and specificity to predict malignancy. However, using quantitative acoustic radiation force impulse elastography, a difference in the deformity and shear velocity of malignant and benign tumors is observed (with increased shear velocity in malignant tumors).
Mammary tumors are treated surgically, although there is no consensus as to the best procedure. Removal of the tumor alone (lumpectomy), simple mastectomy (removal of the affected gland only), modified radical mastectomy (removal of the affected gland and those that share lymphatic drainage and associated lymph nodes), and radical mastectomy (removal of the entire mammary chain and associated lymph nodes) all have their proponents. In dogs, the more involved procedures have not prolonged survival compared with the others, and the advantages of the simpler procedures are obvious. In cats, radical mastectomy has increased the disease-free interval but not survival time.
In theory, the use of anticancer drugs to combat micrometastatic disease (adjuvant chemotherapy) is a reasonable consideration. However, chemotherapy has not been shown to be an effective treatment for mammary tumors in dogs. Part of the difficulty of evaluating the response to adjuvant chemotherapy relates to the fact that only about half of the canine mammary tumors diagnosed as malignant on histopathologic examination actually behave that way. Cyclooxygenase inhibitors (eg, deracoxib) have been shown to exert antiangiogenic and antitumor activities on many types of malignant tumors. A synergistic effect has been described when treating human breast cancers with deracoxib and doxorubicin in vitro. Deracoxib strongly potentiates doxorubicin-caused G0/G1 arrest in cell cycle progression and increases the induction of apoptosis. Deracoxib also enhances the antiproliferative effect of doxorubicin by modulation of Bcl-2 expression.
Clinical research is needed to examine whether the synergism between deracoxib and doxorubicin could result in an effective clinical treatment for canine mammary neoplasia at relatively lower doses of doxorubicin with fewer side effects. A combination of doxorubicin and cyclophosphamide has been used with limited efficacy in cats. Neither radiation therapy nor anti-estrogenic compounds have been effective.
Use of the NSAID piroxicam (0.3 mg/kg/day, PO) as a single agent has been beneficial in treating inflammatory mammary carcinoma, a subtype of mammary tumor in dogs that has been very difficult to manage by surgical or medical means. This is in step with current interest in metronomic low-dose therapy in other malignancies for an antitumor and anti-angiogenic effect.
The prognosis is based on multiple factors. In dogs, most mammary tumors that are going to cause death do so within 1 year. Sarcomas are associated with shorter survival times than carcinomas. Other factors, including size of tumor, lymph node involvement, and nuclear differentiation, also affect the prognosis. In cats, tumor size is important; cats with tumors >3 cm in diameter have a median survival time of 6 months, but cats with tumors <2 cm in diameter have a median survival time of >4 years.
Current dogma is that prepubertal ovariectomy or ovariohysterectomy will reduce the lifetime risk for mammary neoplasia in dogs. However, a systematic review of the literature based on Cochrane guidelines found that the association between the age at spaying and the risk of mammary neoplasia was weak.
It it important to note that prepubertal gonad removal may also increase the lifetime risk for other cancers (eg, lymphoma, osteosarcoma, hemangiosarcoma).
Histologic diagnosis after tumor removal is critical to accurately identifying the disease, developing a correct treatment plan, and providing the client with the most realistic prognosis.