Prognosis, treatment of canine mammary tumors

Q. What are the facts and figures for mammary tumors in dogs?

A. Dr. Antony S. Moore gave an excellent lecture on Diagnosis and Management of Dogs with Mammary Tumors at the 2007 American College of Veterinary Medical Forum in Seattle. Here are some relevant points from that lecture:

Mammary tumors are the most common neoplasm in intact female dogs and account for approximately half of all neoplasms in them. Mammary neoplasms are uncommon in male dogs, accounting for less than 1 percent of these types of tumors. The incidence of mammary tumors is higher in dogs than in any other domesticated animal and is three times the incidence in humans.

Approximately half of the tumors are malignant, and half have metastasized by the time they are initially diagnosed.

Sex hormones certainly play a role in development of mammary tumors in the bitch. Intact females have a seven-fold increased risk of developing mammary cancer compared to neutered females. The age when ovario-hysterectomy takes place is directly proportional to the risk of developing mammary cancer. Data clearly indicate the preventive role of ovariectomy prior to the second estrus.

When only the dogs that had two or more estrus cycles before spaying are considered, there is still a benefit to earlier spaying. If they were spayed before 2.5 years of age, then the risk was 6 percent of those dogs not spayed at all; (that approximates to the 8 percent quoted for one estrus cycle). If they were older than 2.5 years, the risk was 40 percent of unspayed dogs, but that difference was not significant. Essentially the greatest reduction in risk comes if you spay before the first estrus, but then, as long as you spay before 2.5 years, the risk is very low.

Two studies showed that after a malignant mammary tumor develops, there is no effect of ovariectomy on tumor progression. In contrast, a recent study showed increases in survival time for dogs that were ovariectomized within two years before mammary-tumor surgery.

Obesity may be a factor in mammary neoplasia in dogs. In one case-controlled study, the risk of mammary carcinoma among ovariectomized dogs was significantly reduced (by 40 percent) in dogs that had been thin at 9 to 12 months of age. Among intact dogs that were thin at that age, however, risk of mammary cancer was not reduced. In contrast, another study showed obesity at 1 year of age almost trebled the incidence of mammary cancer in intact dogs. In that study, dogs with a higher intake of red meat in their diet were at higher risk for developing mammary cancer.

Obesity and feeding a high-fat diet the year before being diagnosed with a mammary cancer had no influence of tumor development. Caregivers should be counseled to ovariectomize their dogs before the first estrus, and to ensure weight control is practiced in at least the first year of life. Ovariectomies performed later in life, while not as protective, should not be discouraged.

Staging and diagnosis

The two most common sites of metastases are lungs and regional lymph nodes. Therefore, staging should include a minimum database of thoracic radiographs, complete blood count (CBC), biochemical profile, urinalysis and an evaluation of regional lymph nodes (axillary and inguinal) by palpation, fine-needle aspiration cytology and (if indicated) biopsy.

Prognostic factors

The prognosis for dogs with mammary cancer is not influenced either by tumor location or number of tumors. Other factors that are not prognostic are number of pregnancies, age at first pregnancy and occurrence of pseudopregnancies. The following are prognostic factors that have been shown in studies to predict survival or the disease-free interval.

Stage of tumors

Dogs with Stage 1 tumors were more likely to survive longer than those with any other stage tumor. This effect of tumor stage was similar in other studies and is detailed in the following tables.

Effect of tumor stage on survival

Effect of tumor stage on survival

Tumor size

This probably is one of the most important prognostic factors for a dog with a mammary mass. Dogs with mammary tumors less than 3 cm in diameter have a significantly better prognosis than dogs with larger tumors. In another study, dogs with tumors larger than 5 cm in diameter were more likely to develop metastases than dogs with smaller tumors and were seven times more likely to die in the first two years after surgery.

Metastasis

Metastases to regional lymph nodes have been associated with an increased risk for tumor recurrence and for decreased overall survival. The presence of distant metastases was found to be prognostically important in other studies. Dogs with no metastases were more than three times as likely to survive one year from diagnosis.

Age

Older dogs have a worse prognosis in some studies. It is unclear if this is due to tumor-related factors or competing risks.

Diet and body weight

In one study, the effect of diet in the year prior to diagnosis on survival after surgery showed that dietary fat and dietary protein together influenced outcome. When dogs were categorized by the percent of total calories they derived from fat and protein, the median survival time for dogs fed a low-fat diet (<39 percent) with protein greater than 27 percent and less than 23 percent was three years, 1.2 years, and six months, respectively. For dogs fed a high-fat diet (>39 percent), there was no difference in survival for the different intake levels of dietary protein. In addition, body conformation one year prior to diagnosis affected survival.

Degree of invasion and ulceration

Dogs with tumors that ulcerate overlying skin have a worse prognosis (shorter overall survival times) than those with tumors without ulceration. Rapid and invasive growth correlates with a worse prognosis, which may be recognized as fixation of the tumor to the underlying skin. Vascular or lymphatic invasion is a poor prognostic factor; dogs with histopathologic evidence of invasion have a shorter median survival.

Histopathologic examination

Several histopathologic grading schemes are of prognostic significance. Important factors include histopathologic classification, degree of nuclear differentiation and the presence of lymphoid accumulation. In general, the more highly differentiated the tumor, the better the prognosis. Poorly differentiated tumors are much more likely to recur than well-differentiated tumors.

The chance of recurrence for poorly differentiated canine mammary tumors is 90 percent; for moderately differentiated tumors, 68 percent; and for well-differentiated tumors, 24 percent. Dogs that have mammary cancer but no evidence of lymphoid cellular reactivity at the time of initial mastectomy have a three-fold increased risk of developing recurrence within two years, compared to those with such reactivity.

Dogs with inflammatory carcinomas also have a poor prognosis. When reviewing a histopathology report, the veterinarian should look for information regarding completeness of the surgical excision, invasion into lymphatics or blood vessels and differentiation of the tumor.

Hormone-receptor activity

Dogs with tumors that are estrogen-receptor and/or progesterone-receptor positive have a better prognosis than dogs with tumors that do not have receptors (i.e., longer disease-free and overall survival times). Receptor-positive tumors are likely to be benign. While presence of estrogen and progesterone receptors was predictive for disease-free survival after surgery in one study, on multivariate analysis the effects of tumor size and histopathologic grade overpowered that effect.

Proliferative activity

Dogs with tumors that showed a high proportion of Ki-67 staining (which is an immunohistochemical marker for cellular proliferation) were more likely to develop metastases in studies. Additionally, Ki-67 staining was inversely related to survival time.

Ovariectomy status

In one study, dogs that were intact at the time of surgery for a mammary carcinoma survived a shorter time (median survival 9.5 months) than dogs ovariectomized within the two years before surgery (median survival 25 months). Dogs ovariectomized more than two years before mammary tumor surgery did not benefit to the same extent.

In addition, dogs that were intact had a higher proportion of solid and anaplastic carcinomas than either group of ovariectomized dogs (80 percent solid carcinomas in intact dogs, compared to 20 percent [<two years] and 7 percent [>two years]).

In another study, dogs that were not intact at the time of diagnosis were 2.5 times more likely to survive two years after surgical excision of the mammary malignancy. In contrast, ovariohysterectomy at the time of tumor removal had no effect on survival in another study, with approximately 60 percent of dogs with malignant tumors dying within two years of surgery whether they were spayed at the time or not.

Duration of tumor presence

Dogs with a mammary malignancy longer than six months were more likely to develop metastases than those with tumors removed soon after diagnosis.

Extent of surgery

The extent of surgery influences neither survival nor disease-free interval. Instead, the histopathologic completeness of surgical margins as assessed by histopathologic examination has been shown to be prognostic for survival, so the best surgery to achieve complete margins is the surgery that should be offered.

Effect of type of surgery on outcome for dogs with mammary tumors

Adjuvant therapy

Dogs with large, invasive or metastatic mammary tumors may benefit from systemic chemotherapy. Appropriate clinical studies are essential to document the efficacy of chemotherapy, but have not yet been reported.

There are indications of activity for different chemotherapy agents from in vitro studies but there is a huge leap from these studies to clinical efficacy. Drugs shown to have in vitro activity or potential clinical efficacy include 5-fluorouracil, cyclophosphamide, doxorubicin, carboplatin, mitoxantrone, paclitaxel and docetaxel.

The finding that normal mammary tissue has no evidence of cyclo-oxygenase-2 (cox-2) expression, and that 24 percent of benign and 56 percent of malignant mammary tumors do express cox-2 had led to speculation that non-steroidal inhibitors of cox-2 may play a role in the treatment of mammary carcinoma and possibly the prevention of new lesions.

In two other studies, mammary carcinomas that were more anaplastic had higher levels of cox-2 expression. In an early evaluation of piroxicam (a non-steroidal anti-inflammatory drug) in the treatment of cancer in dogs, one of three dogs with mammary carcinoma had a partial response to therapy.

Dr. Hoskins is owner of Docu-Tech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: jdhoskins@mindspring.com