Center of Clinical Comparative Oncology (C3O), Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden
Canine Mammary Tumors
Mammary tumors (MTs) are the most common type of neoplasia in entire female dogs, representing approximately 50% of all tumors reported. The canine MT malignancy rate is about 50%. Half of these have metastasized by the time of clinical presentation. Mean age of onset of MT is approximately 8 years. The incidence increases with age and varies by breed, with high-risk breeds including English Springer Spaniel and Dachshund and low-risk breeds being the Rough-Haired Collie, clearly showing both high-risk and potentially preventive (genetic) phenotypes. Sex hormone stimulation increases the risk of MTs in dogs, as well as other species including humans. Ovariohysterectomy in dogs prior to 2 years of age greatly reduces the risk of mammary tumors. Obesity at young age and consumption of homemade meals has been associated with increased risk of developing MT.
The highly detailed present histological classification aims to internationally standardize terminology and nomenclature of canine MTs. The classification follows the dedifferentiation process, starting with malignant tumors most closely resembling the normal structure of the mammary gland and ending with poorly differentiated tumors with no glandular structure. Prognosis is closely correlated to the level of differentiation. This is very important to recognize in the clinical situation, to more easily communicate prognosis and treatment planning.
In parallel with breast cancer research in humans, there have been several reports showing the benefit of predicting prognosis with different immunohistochemistry markers in dogs. The most obvious is the expression of the sex hormone receptors, estrogen receptor (ER) and progesterone receptor (PR). There is a clear tendency towards worse prognosis and higher malignancy grade with lower expression of ER and PR.
Although easy to perform, aspirates of an MT unfortunately have little chance of predicting malignancy in dogs.
Clinical staging is important in determining prognosis. Bitches with high-stage disease, according to the World Health Organization (WHO) tumor, node, metastasis (TNM) staging criteria, carry a poor prognosis. Therefore, treatment planning should always rely on proper staging procedure. This includes a general physical examination to ascertain tumor size, as this is a significant parameter predicting clinical outcome in itself. Palpation of the regional lymph nodes should always be performed as detected lymph node metastasis carries a worse prognosis. If enlarged, an aspirate should be performed to detect metastasis on cytology prior to surgical planning. The second most common organ for metastasis of MT is the lungs. In 25% of carcinomas and in the majority of sarcomas, pulmonary metastasis usually occurs as the disease progresses.
Management and Prognosis
The treatment of choice for MT is surgery, the extent ideally being guided by clinical stage and histological grade. It is important to bear in mind, however, that overall survival is (surprisingly) reportedly not influenced by the extent of the surgical procedure in dogs. If the surgery does not achieve clean margins, the outcome is always worse. The chosen surgical procedure should always aim to obtain free surgical margins. Delaying surgery is not advisable, as tumor size is a significant prognostic marker. Tumors < 1 cm in diameter have a favorable overall survival; tumors 2–3 cm in size still have a fair prognosis with reported overall survival of 22 months. Conversely, with tumors > 3 cm, the outcome is more guarded, with survival times of approximately 1 year after surgery. All tumors > 0.5 cm in diameter should be excised and submitted for histopathological review. If the tumor has a high grade or is reported to have incomplete margins, new, more aggressive surgery should always be considered.
Adjunct chemotherapy in canine MTs has yet to be proven to be as beneficial as in human breast cancer. Inevitably, small sample size, retrospective studies, and the large number of benign tumors have made it hard to show any significant benefits compared to surgery alone. In 2012, a prospective clinical trial was presented in which dogs with aggressive mammary carcinoma (T3N1-2M0-1) were treated with surgical excision alone (n = 7) or with surgery and adjuvant carboplatin for three cycles at a dose of 300 mg/m2 ± COX-2 inhibitors (n = 22). Different proposed adjuvant treatments associated with surgery led to a statistically significant longer overall survival compared to surgical treatment alone.
Radiotherapy and Hormonal Therapy
Adjuvant radiation and antiestrogens, such as Tamoxifen®, have not shown any benefits compared to surgery alone in dogs.
Feline Mammary Tumors
Many of the features described for canine MTs also apply to the cat. Below, more specific characteristics for the feline disease are described.
Mammary tumors are more often malignant in cats compared to dogs. The frequency of malignancy in cats is reported to be at least 80%. Mammary tumors are the third most common cancer in cats, outnumbered only by hematopoietic neoplasms and skin tumors.
Siamese and domestic short-hair cats are reported to have a higher incidence rate.
Mammary neoplasia has been reported in cats from 9 months to 23 years of age, with a mean age of occurrence of 10–12 years.
As in dogs, hormonal influence is also reported to be part of the pathogenesis in feline MTs. The risk of developing MTs is seven times higher in intact compared to oophorectomized cats. No protective effect of spaying performed after 2 years of age is seen. However, cats spayed at less than 1 year old do still develop MTs, so the effect of early neutering does not completely eliminate the risk of MTs. There is a strong association between prior use of progesterone-like drugs and development of benign and malignant MTs. Positive ER status has been reported to be as low as 10% in feline tumors, far lower than in dogs and humans. This reflects the higher percentage of malignant tumors seen in the cat.
The most common histological classification is adenocarcinoma, accounting for over 85% of tumors. Vascular invasion and, to an even higher degree, lymphatic invasion may be present upon histological examination and are of prognostic significance as they suggest metastatic propensity. Rare benign mammary gland dysplasias (fibroadenomatous hyperplasia) are an important part of a differential diagnosis and may sometimes resemble a severe clinical condition.
Of specific importance when staging feline MT is to describe the primary tumor (i.e., define T) and evaluate the presence of metastasis (i.e., define M). For the primary tumor, number of tumors, size (of prognostic significance on its own), location, and signs of infiltrative growth (fixation to skin/underlying fascia) should be examined. The size of the tumor influences the prognosis, tumors < 3-cm diameter being associated with better survival rates compared to those > 3-cm. As in the dog, staging is performed.
Management and Prognosis
The cat has four pairs of mammary glands. The two cranial mammary glands drain to the axillary lymph node, while the two caudal mammary glands drain to the superficial inguinal node. In contrast to dogs, in cats there has been suggestion of communication between the two mammary chains, across the midline. This has, however, not been confirmed in live imaging of healthy animals. Drainage may vary between normal glands and glands with MTs, making it difficult to know the precise drainage pathway. Consequently, staged bilateral mastectomy is sometimes recommended, performed 3–4 weeks apart to allow healing and relaxation of stretched skin. Simultaneous bilateral mastectomy should be avoided, as several studies report no significant (or small) benefit in overall survival and the procedure will most likely cause unnecessary postoperative discomfort. If the tumor has invaded the abdominal musculature, the excision must include a portion of the abdominal wall. Simultaneous ovariohysterectomy has not been proven to decrease incidence of recurrence or promote overall survival, but will prevent uterine disease (e.g., pyometra, metritis) and significantly decrease female hormonal influence on existing lesions.
As in dogs, there is no evidence that radiotherapy is beneficial in improving clinical outcome in feline MTs compared to surgery alone, and it is rarely used in an adjuvant setting.
Because of the aggressive nature of feline MTs, with significantly reduced overall survival if tumor size exceeds 3 cm, there have been many attempts to use adjuvant chemotherapy following surgery or sometimes as the only therapy in non-resectable cases. In a larger retrospective, multicenter study on 67 cats with histologically confirmed mammary gland adenocarcinomas treated with adjunctive doxorubicin, it was shown that cats that completed the adjunctive doxorubicin protocol had significantly improved survival. The major side effects of these protocols have been anorexia and mild myelosuppression. Reducing the dose of doxorubicin or substituting it with mitoxantrone may limit toxicity to an acceptable level. 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.
References are available upon request.