Abstract

Mammary tumors are common in older intact female dogs. Clinically these tumors appear as discrete mass(es) of various sizes in the mammary glands. Systemic signs are rare and depend of stage of disease at diagnosis. Complete work-up and staging should be performed prior to surgery; and these results as well as results from histopathologic evaluation are incorporated into decisions regarding systemic therapy.

Epidemiology

Mammary tumors are the most common type of tumors in intact female dogs and represent 41.7% of all tumors in intact female dogs according to the California Animal Neoplasia Registry (CANR).¹ The overall incidence of canine mammary gland tumors in the United States, however, has been reduced significantly because of the common practice of performing OHE at an early age. However, mammary tumors remain a major cause of illness and premature death in dogs in other countries around the world where OHE is not routinely advocated and performed.

Etiology

The causes/risk factors for mammary tumors are multi-factorial; hormonal exposure, age and genetics are important influences for a dog's life time risk for mammary tumors.¹

Hormonal Factors

The duration of exposure to ovarian hormones early in life determines the overall mammary cancer risk. The risk of developing mammary gland tumors increases from 0.5% to 8%, and to 26%, depending on whether the OHE is performed before the first, second, or any estrus thereafter, respectively.² Administration of exogenous hormones, both estrogens and progestins also increases the risk of tumor development.³ The tumorigenic effects of estrogen in human breast cancer is thought to be mediated via their receptor binding and enhanced production of growth factors resulting in increased cellular proliferation. Mechanisms involved in progesterone-induced mammary gland tumors include an up-regulation of growth hormone (GH) production within the mammary gland. GH has direct growth stimulatory effects on mammary tissue but also has indirect effects via insulin-like growth factor I (IGF-I).⁴ A significant portion of mammary tumors, especially benign and well differentiated carcinomas express hormone receptors (HR) both ER and/or PR suggesting a continued dependence on hormones.⁵

Age

Even though the crucial exposure to hormones occurs at a very early age, mammary tumors are usually not clinically obvious until much later in life. Most affected dogs are middle age and older. Malignant tumors are rare in dogs younger than 5 years old. The tumor risk increases incrementally each year and plateaus around 11–13, depending on the breed.⁶ Dog with malignant tumors are older than dogs with benign tumors.⁷

Genetics

Certain breeds are at increased risk of developing mammary gland tumors. The breeds reported to be at increased mammary cancer risk vary between study and geographic location, but in general the smaller breed dogs tend to be more commonly affected. Of the larger breeds it is the English Springer Spaniels, Brittany Spaniels, English Setters and German Shepherds that are most consistently overrepresented. The fact that certain breeds have an increased risk of developing mammary gland tumors suggests a genetic component. A common genetic mutation has not been identified, however.

Clinical Features

Mammary tumors appear as discrete palpable masses in the mammary glands. The caudal 2 glands are affected more often than the more cranial glands; however, multiple synchronous masses are common; up to 70% of intact female dogs have more than one tumor at diagnosis.⁷ Therefore, all mammary glands should be carefully palpated and all tumors regardless of size should be recorded for surgical planning. Dogs diagnosed with early stage disease and small tumors are likely to be systemically healthy in terms of their tumors, while dogs diagnosed later in the course of disease may have large primary tumors, enlarged lymph nodes or systemic signs due to distant metastasis. Dogs with inflammatory mammary carcinoma, a relatively rare subtype of anaplastic carcinomas, may present with acute onset painful, extensive swelling of the glands; sometimes the entire mammary chain(s) is involved, mimicking mastitis.⁸ However, the presentation and progression of most canine mammary tumors is less dramatic. In fact canine mammary tumors represent a wide range of histologies from benign to highly malignant with the corresponding clinical behavior. It is estimated that approximately 40–50% of all mammary tumors are malignant. However the % of malignancy depends on the size or stage at clinical detection. A recent study found a strong direct correlation between size and malignancy. Most (98%) small tumors (< 1 cm) were benign, but the risk for being malignant increased incrementally with each size category and 50% of all tumor > 3 cm were malignant.⁷ A progression form benign to malignant tumors was noted with increasing tumors size suggesting a histological continuum where malignant tumors develop from specific pre-malignant lesions within benign lesions. This progression, however, does not occur in all dogs, some dogs with indolent small benign tumors do not change, while others may retain a benign histology despite continuing to grow.

Histopathological Classification

In addition to being characterized as benign and malignant mammary tumors are also classified according to tissue type of origin. The classification system for canine mammary tumors has undergone several revisions, the latest in 2011, as new insight into behavior and specific entities are described.⁹ The mammary gland consists of 3 distinct cell types/tissue types: epithelial, myoepithelial and mesenchymal. Tumors may consist of only one cell type or a combination of 2 different cell types where none, only one or both components are malignant. A combination of epithelial and myoepithelial cell type constitutes a "complex" tumor, while the combination of epithelial and mesenchymal cell types constitutes a "mixed" tumor. In addition, the epithelial tumors are also graded, as low grade (I), intermediate grade (II) or high grade (III).⁹ Thus the histological spectrum is wide and heterogeneous. Furthermore, the clinical behavior of all these subtypes may not be completely characterized as of yet. It may therefore be difficult to know how this information should be incorporated into treatment planning. However, the prognosis is determined by the most aggressive component/subtype, and simple carcinomas of various grades are the most common malignant tumors in the dog. Several of the prognostic studies have evaluated treatment and outcome of dogs with this most common type of malignant mammary tumors.

Diagnostics and Staging

A complete work-up and staging including blood work (complete blood counts and serum chemistry profile) and 3-view thoracic radiographs should be performed as part of the surgical planning to evaluated general health and ensure that the dog is an appropriate anesthetic and surgical candidate. All tumors should be measured and recorded and the draining lymph nodes (axillary: glands 1, 2 and 3; inguinal: glands 3, 4 and 5) should be assessed carefully by palpation and aspirated if possible. Cytological exam of the draining lymph nodes is an effective and sensitive screening method to stage the local lymph nodes. Cytology may be used to differentiate between benign or malignant primary tumors, but surgical biopsies are required for an accurate histopathological diagnosis. An incisional biopsy is often not performed prior to surgical excision, but is performed as part of the tumor removal (excisional biopsy). All tumors should be removed and biopsied in dogs with multiple tumors. Several sections should be taken from large tumors to ensure complete histopathological assessment of the entire lesion. Margins should be labeled and inked. The inguinal lymph nodes are typically included when the caudal mammary glands are excised en-bloc. Care should be taken to ensure that these lymph nodes are identified and included when the resected tissues are trimmed and processed for histopathological exam.

Staging System

A modified WHO staging system is used to stage canine mammary tumors. This staging system is based on the TNM system and includes information regarding tumor size, lymph node status and distant metastasis. Table 1 depicts a modified WHO staging system for epithelial tumors (excluding inflammatory carcinomas).¹⁰

Table 1.

References

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