Current recommendations for mammary gland tumors in dogs

Mammary gland tumors remain one of the most common cancers in our canine patients. Despite the high incidence, there have been few significant advances in the treatment of these tumors. In this article, I review the current standard of care and present new insights into the biology of these tumors.

Biologic behavior

In dogs, the biologic behavior of mammary gland tumors is highly variable. The rule of thumb has been that 50 percent of mammary gland tumors are benign, and of the 50 percent that are malignant, half can be cured by surgery alone. This means that 25 percent of patients are at high risk of metastasis and require therapy beyond surgery alone.

It is well-documented that early ovariohysterectomy (OHE) significantly decreases the risk of development of mammary gland tumors in the future. Body mass index as a juvenile may also influence the risk for future development of these tumors. Dogs assessed as being lean at 1 year of age have a lower risk of developing mammary gland cancer. New areas of interest include looking into dietary manipulation as another factor to consider in preventing these tumors.

For those dogs that do develop mammary tumors, it has been shown that up to 60 percent will develop multiple tumors, and dogs that have had a malignant tumor are at higher risk of developing a second malignant tumor compared with dogs with benign tumors. However, these separate primary tumors likely share a common etiology. It has been suggested that mammary tumors in dogs develop as a result of a phenomenon known as field carcinogenesis, which involves the idea that multiple tumors are the result of all of the mammary tissue being exposed to the same hormonal environment.

Prognostic factors

Well-known prognostic factors include tumor size, tumor type, grade of tumor, degree of differentiation, stage and the presence of vascular or lymphatic invasion. Equally important to note, factors that have not been shown to be prognostic include tumor location, number of tumors or the type of surgery performed.

Most studies have shown that tumors 3 cm or less have a better prognosis, although a recent study showed the same to be true of tumors up to 5 cm.1 In this study, tumors > 5 cm were more likely to be associated with nodal metastasis, as were tumors that were present less than six months before surgery. Results also indicated that an OHE performed at the time of tumor removal significantly improved the two-year survival rate. These findings indicate that while tumor size is an important prognostic factor, it is necessary to look at other variables when estimating survival times.

Tumor types that have a negative prognosis include mammary gland sarcomas and inflammatory mammary gland tumors. Mammary gland sarcomas (fibrosarcoma or osteosarcoma) are uncommon but have been reported. The average survival time for mammary gland sarcomas of any kind is short, usually between 9 and 12 months. Inflammatory mammary gland tumors are highly aggressive and typically present as a rapidly growing tumor with ulceration, edema and erythema. On histopathologic examination, these tumors are poorly differentiated, with invasion of dermal lymphatics. Treatment typically consists of palliative care only, and the survival time for these patients is one to two months. Surgery is not recommended for patients with this tumor type.

Tumor grade has also been used as a prognostic indicator. Tumors that are classified as high grade have a high mitotic index, poor nuclear differentiation and significant necrosis. However, pathologists have not adopted a standard grading scheme for mammary tumors, so often the grade must be inferred from the microscopic description.

In addition, other molecular factors such as estrogen and progesterone receptor status, proliferative indices and the presence of certain gene mutations can predict biologic behavior. These factors have advanced our understanding of the biologic behavior and progression of mammary gland tumors but are not widely available for use in routine evaluation of clinical patients. In a recent study, 113 dogs with both malignant and benign mammary tumors were evaluated for the presence of estrogen and progesterone receptors.2 Almost all of the benign tumors had both estrogen and progesterone receptors, but in the malignant tumors, only 50 percent had estrogen receptors and 70 percent had progesterone receptors. Tumors that were positive for both types of receptors were more likely to be < 5 cm and were less likely to have metastasized at the time of diagnosis. Particularly, the dogs that had the highest one-year survival rate were the dogs that were positive for progesterone receptors. The results of this study suggest that determining the presence of these hormone receptors may help predict tumor behavior.

Lumpectomy vs. mastectomy

In general, the goal of surgery is to completely excise the tumor with the simplest surgery possible. It is important to take into account the size and location of the tumor, whether the tumor is movable and whether there are multiple tumors or palpable lymph nodes. For larger tumors requiring a more aggressive surgery such as a regional mastectomy, the pattern of lymphatic drainage may also be important.

A recent prospective study found that 58 percent of dogs with a malignant tumor removed via a regional mastectomy developed a second tumor in an ipsilateral gland.3 The researchers' conclusion was that all malignant tumors should be removed with a radical mastectomy. This recommendation may prevent the development of future tumors but does not change the rate of local recurrence provided a wide excision is achieved. In addition, it should be noted that the dogs in this study were all intact females at the time of entry and were not spayed during the course of the study, which may have influenced the outcome.

Lumpectomies are generally reserved for those tumors that are small (< 0.5 cm), movable and benign. If a malignant tumor is removed via a lumpectomy and the margins are inadequate (< 1 to 2 cm), a second surgery to widen the margins is recommended. For tumors that are larger (1 cm) and localized within a single gland, a mammectomy should be considered. A regional or radical mastectomy is generally reserved for those dogs with larger tumors or that have multiple affected glands. If the tumor is fixed to the underlying tissue or skin, it is also important to remove skin and abdominal wall muscle or fascia to obtain an adequate excision.

If either the axillary or inguinal lymph nodes are enlarged, they should be removed and/or biopsied at the time of surgery. When the axillary lymph node is not enlarged, it can be difficult to find by surgical dissection, so removal of the node in these cases is not recommended. The inguinal lymph node is closely associated with the fifth mammary gland and is removed whenever the fifth gland is excised regardless of whether it is enlarged or not.

To spay or not to spay

There is still the debate as to whether or not an OHE at the time of tumor removal in intact dogs improves survival time. Early studies did not support the recommendation of an OHE at the time of diagnosis. However, two recent studies were able to demonstrate a survival benefit for those dogs that were spayed at the time of diagnosis.1,4 It is logical to consider that an OHE would improve survival time since it removes the major source of estrogen and progesterone production. In a sense, it could be compared to using an anti-estrogenic drug such as tamoxifen. It would be expected that dogs that had estrogen or progesterone receptor positive tumors would benefit most from an OHE as this would eliminate a source of hormonal stimulation for any remaining tumor cells.

To give or not to give adjuvant therapy

Given that 25 percent of dogs with mammary gland tumors cannot be successfully treated with surgery alone, it is desirable to consider some type of adjuvant chemotherapy for these patients. However, there is not a standard approach in treating canine mammary gland tumors with chemotherapy. In people, the most effective drugs are the anthracyclines (i.e., doxorubicin) and the taxanes (i.e., paclitaxel), either alone or in combination with other drugs. Doxorubicin is frequently combined with cyclophosphamide as a first-line adjuvant therapy for high-risk human patients.

In veterinary medicine, we have taken a similar approach to adjuvant therapy, though the data to support the use of chemotherapy are scarce and there are conflicting reports in regards to efficacy. Drugs that have been evaluated include cyclophosphamide, 5-fluorouracil, doxorubicin, docetaxel and gemcitabine.5,6 Given the small number of patients in these studies, it is difficult to ascertain the efficacy of chemotherapy. Anti-estrogenic drugs such as tamoxifen have also been evaluated but have not yet proved to be of benefit and carry a high risk of side effects including stump pyometra.

Despite the limitations, oncologists still recommend chemotherapy for high-risk patients and for those with metastatic or nonresectable disease. The protocol is often determined by an oncologist's clinical experience as well as the specifics of the case. It is hoped that more effective targeted therapies will be developed as we continue to explore the molecular basis of these tumors.

Dr. Cronin earned her DVM degree from Cornell University in 1990. She completed an internship at the Animal Medical Center in New York and a medical oncology residency at North Carolina State University. She is a diplomate of the American College of Veterinary Internal Medicine in the specialty of oncology. After completing her residency, she was lecturer at the University of Pennsylvania Veterinary Teaching Hospital and a medical oncologist at Angell Memorial Animal Hospital in Boston. In 2001, she co-founded the New England Veterinary Oncology Group in Waltham, Mass.

References:

1. Chang SC, Chang CC, Chang TJ, et al. Prognostic factors associated with survival two years after surgery in dogs with malignant mammary tumors: 79 cases (1998-2002). J Am Vet Med Assoc 2005;227(10):1625-1629.

2. Chang CC, Tsai MH, Liao JW, et al. Evaluation of hormone receptor expression for use in predicting survival of female dogs with malignant mammary gland tumors. J Am Vet Med Assoc 2009;235(4):391-396.

3. Stratmann N, Failing K, Richter A, et al. Mammary tumor recurrence in bitches after regional mastectomy. Vet Surg 2008;37(1):82-86.

4. Sorenmo KU, Shofer FS, Goldschmidt MH. Effect of spaying and timing of spaying on survival of dogs with mammary carcinoma. J Vet Intern Med 2000;14(3):266-270.

5. Marconato L, Lorenzo RM, Abramo F, et al. Adjuvant gemcitabine after surgical removal of aggressive malignant mammary tumors in dogs. Vet Comp Oncol 2008;6(2):90-101.

6. Simon D, Schoenrock D, Baumgartner W, et al. Postoperative adjuvant treatment of invasive malignant mammary tumors in dogs with doxorubicin and docetaxel. J Vet Intern Med 2006;20(5):1184-1190.