+ General Considerations

• Mammary tumors are the most common tumor in female dogs, accounting for 42% of all tumors and 82% of reproductive tumors
• Mean age 6-10 years and rare < 4 years
• Breed predisposition: Pointers, Irish Setter, Brittany Spaniel, English Springer Spaniel, Labrador Retriever, Great Pyrenees, Samoyed, Airedale Terrier, Miniature and Toy Poodle, Dachshund, and Keeshond
• Mammary tumors in male dogs are usually malignant
• Multiple mammary tumors are common: 672 female entire Beagles followed for life-span with 71% having at least 1 mammary tumor and 61% with > 1 mammary tumor

+ Benign Mammary Tumors

• Benign tumors include adenoma (simple, complex, and basaloid), fibroadenoma, mixed tumor, and duct papilloma
• Mixed tumor is common and contains epithelial and mesenchymal components (i.e., cartilage, bone, or fat)

+ Malignant Mammary Tumors

• 41%-53% of mammary tumors in female dogs are malignant
• Life-time risk of female intact dog developing a malignant mammary tumor is 23%-34%
• However, histologic evidence of malignancy does not imply malignant course of disease as only 4.4% cases of malignant mammary carcinoma are fatal
• Revised WHO classification of malignant mammary tumors ranks tumors by malignant potential and may offer some prognostic information:
• Carcinoma in situ
• Complex carcinoma
• Simple carcinoma (i.e., tubulopapillary, solid, and anaplastic)
• Special carcinoma types (i.e., spindle cell, mucinous, lipid-rich, and SCC)
• Sarcoma (i.e., FSA, OSA, and other)
• Carcinosarcoma
• Carcinoma or sarcoma in benign tumor
• Secretory carcinoma is a rare mammary tumor characterized by the presence of intracellular and extracellular eosinophilic excretions
• Sarcomas are uncommon and may arise from myoepithelial tissue which have undergone malignant change or from intralobular connective tissue
• Sarcomas do not arise from preexisting benign mixed mammary tumors
• Malignant tumors metastasize by hematogenous and lymphatic routes
• Metastatic sites: regional lymph nodes, lungs, adrenal gland, kidney, heart, liver, bone, brain, and skin
• Metastasis to the lungs is more common with primary tumors in mammary glands 4-5

+ Inflammatory Carcinoma

• Inflammatory mammary carcinomas account for 4%-18% of malignant mammary tumors
• Inflammatory mammary carcinomas are poorly differentiated with extensive mononuclear and leukocyte cellular infiltrates, edema, rapid growth and metastasis, and invasion of cutaneous lymphatics with marked edema and inflammation
• Primary and secondary inflammatory mammary carcinomas:
• Primary: acute onset of inflammatory signs
• Secondary: inflammatory signs develop after excision of mammary tumor or present for > 4 months
• Dogs with inflammatory mammary carcinoma were significantly older than dogs with other mammary tumors
• Development of inflammatory carcinoma is associated with diestrous phase of the estrous cycle and hence progesterone may play a direct or indirect role in the development of inflammatory mammary carcinomas
• 96% have regional lymph node and 32% have thoracic metastasis at diagnosis, and 100% have regional lymph node and 62% have thoracic metastasis at euthanasia
• Primary inflammatory mammary carcinomas have a poorer prognosis than other mammary tumors with a more aggressive behaviour, faster growth rate, and poor clinical condition

+ Ovariohysterectomy

• Reduces the risk of mammary neoplasia with an incidence of 0.5% if before neutered before the 1st estrous, 8% before the 2nd estrous, 26% after 2 ovarian cycles, and no protective effect after 2.5 years
• Ovariohysterectomy is not indicated if > 2.5 years as does not affect biologic behaviou

+ Hormones and Hormonal Receptors

• Estrogen and progesterone receptors are present in 70% of benign and 50% of malignant mammary tumors
• Tumors which lack of hormone receptors are more aggressive and less differentiated
• EGF and TGF are associated with estrogen and progesterone receptors and may play a role in the development of mammary tumors

+ Exogenous Progestins

• Progesterone and synthetic progestins (i.e., medroxyprogesterone acetate) induce lobuloalveolar development of mammary glands with hyperplasia of secretory myoepithelial elements
• Exogenous progestins stimulate multiple benign nodules
• Estradiol stimulates ductal growth, but has not been associated with mammary tumor development
• Mammary tumor risk increases with the combined use of estrogens and high dose progestins or drugs with combined progestagenic-estrogenic activity
• Norwegian Canine Cancer Register 1990-1998: 25% of bitches and 5% dogs with mammary tumors were treated with medroxyprogesterone acetate
• 19-nortesterone causes mammary carcinoma in 40% of treated dogs
• Exogenous progestins induce growth hormone production which may influence mammary gland tumor development by proliferation and transformation of susceptible mammary epithelial cells

+ Diet

• High fat diet and obesity increase the risk of mammary tumor development in dogs, rodents, and humans
• Risk of mammary neoplasia is lower if dogs are thin at 9-12 months
• Obesity at 12 months is a risk factor for development of mammary tumors
• Nutritional factors may also play a role as home-made meals (high in beef and pork and low in chicken) are associated with an increased risk of mammary neoplasia

+ General Considerations

• Single or multiple masses within the mammary chain developing simultaneously or subsequently
• Mammary mass can be associated with glandular tissue (common) or nipple
• 65%-70% mammary neoplasia occurs in mammary glands 4 and 5 due to greater volume of mammary tissue
• Benign tumors are often small, well-circumscribed, and firm
• Malignant tumors often have rapid growth, ill-defined borders, fixation to skin or underlying tissue, and ulceration or inflammation
• Inguinal lymph node metastasis can spread via pudendal lymphatics to sublumbar lymph nodes and cause tenesmus
• Vesicopustular dermatitis is associated with cutaneous metastasis from mammary carcinosarcoma

+ Inflammatory Mammary Carcinoma

• Clinical signs: pain, anorexia, weight loss, generalized weakness, and polyuria-polydipsia
• Inflammatory mammary carcinomas were apparent significantly earlier after the last estrus (52 days v 137 days) and is associated with diestrous phase of the estrous cycle and hence progesterone may play a direct or indirect role in the development of inflammatory mammary carcinomas
• Inflammatory carcinomas are diffusely swollen with poor demarcation between normal and abnormal tissue
• Physical examination findings: diffuse involvement of both mammary chains in 55%, palpable mammary mass in 24%, and pelvic limb edema and lameness in 61%
• Lymphedema in the pelvic limb adjacent to inflammatory carcinoma can be observed due to occlusion of lymphatics and retrograde growth of tumor
• DDx: acute mastitis (localized and associated with estrous or false pregnancy compared to firm and diffuse swelling)

+ General Considerations

• Physical and rectal examination to assess extent of disease
• Hematology and serum biochemistry
• Coagulation profile is recommended in dogs with suspected malignant tumors due to the risk of DIC
• FNA but difficult to differentiate benign and malignant mammary tumors
• FNA is useful in the diagnosis of inflammatory carcinoma and metastatic mammary tumors to regional lymph node
• Thoracic radiographs for metastatic disease
• Caudal abdominal radiographs or ultrasonography for sublumbar lymph node metastasis
• Biopsy if inflammatory mammary carcinoma is suspected
• Ultrasonography: benign tumors have regular margins and are spherical-to-ovoid shaped with a homogenous echogenic pattern while malignant tumors have irregular margins with heterogenous internal echogenicity

+ Chemotherapy

• No known effective adjuvant chemotherapy protocol for malignant or metastatic mammary tumors
• Doxorubicin and cyclophosphamide or cisplatin has some antitumor effect against mammary ADC
• Doxorubicin associated with PR with duration of 12 and 15 months in 2 dogs with metastatic mammary ADC
• Doxorubicin has better efficacy than platinum drugs and carboplatin and cisplatin have equivalent efficacy in vivo and efficacy was not affected by cell type (i.e., ADC, solid carcinoma, and mixed )
• 5-fluoroucil and cyclophosphamide combination significantly improves survival time in dogs with high-risk mammary carcinomas following surgical resection compared to surgery alone (MST 24 months v 6 months)
• Piroxicam combined with radiation therapy is the best treatment for dogs with inflammatory mammary carcinoma
• Bisphosphonates and palliative radiation therapy for metastatic bone lesions

+ Radiation Therapy

• Role of radiation therapy with incompletely resected mammary tumors has not been investigated
• Short-term regression reported for radiation therapy in dogs with inflammatory mammary carcinoma

+ Immunotherapy

• Non-specific immunomodulation with levamisole and Corynebacterium parvum with BCG combined with surgery has no significant effect compared to surgery alone
• Liposome-encapsulated muramyl-tripeptide phosphatidylethanolamine, a derivative of mycobacterial cell wall, is not effective in dogs with invasive mammary carcinoma

+ Hormonal Therapy

• Hormonal therapy is controversial
• Hormonal therapy may be ineffective due to lack of steroid receptors in malignant mammary tumors
• Hormonal therapy may be indicated for tumors expressing estrogen, progesterone, or prolactin receptors
• Tamoxifen is a mixed anti-estrogen with both agonist and antagonistic effects which are species dependent
• Tamoxifen is used in women with estrogen receptor-positive breast cancers
• Tamoxifen has antiproliferative activity in vitro and limited degree in vivo with response in 0% (0/10) and 71% (5/7) dogs with inoperable and metastatic tumors, respectively
• Mean survival time 4 months
• Adverse effects preclude routine use: vulvar swelling, vaginal discharge, incontinence, UTI, stump pyometra, and signs of estrous
• LHRH analogue (Goserilin) reduced circulating levels of estradiol and progesterone and had some antitumor activity in 53% (18/34) dogs with estrogen receptor-positive mammary carcinoma

+ General Considerations

• Surgical excision of mammary tumors is recommended
• Contraindications: metastatic disease or inflammatory carcinoma
• Inflammatory carcinoma often advanced at diagnosis and recurrence common
• Excisional techniques include: excisional biopsy, local mastectomy, regional mastectomy, unilateral mastectomy, and simultaneous or staged bilateral mastectomy
• No difference in recurrence rate or survival time of simple mastectomy and radical mastectomy
• Radical surgery may reduce risk of de novo tumor development and malignant transformation of benign lesions, however, radical mastectomy is associated with greater morbidity and over-treatment for both benign and malignant mammary tumors
• Aim: removal of all neoplastic tissue with simplest procedure
• ± ovariohysterectomy

+ Excisional Biopsy

• Indications: small (< 0.5 cm), firm, superficial, and non-fixed mammary masses
• Excisional biopsy is preferred with removal of a margin of normal tissue and 2-layer closure
• Wide excision is recommended with feline mammary tumors due to malignancy

+ Local Mastectomy

• Indications: centrally located lesions, lesions > 1.0 cm, and masses with any degree of fixation
• Local mastectomy is the removal of a single mammary gland
• 2 elliptical incisions performed around the mammary gland
• Soft tissue dissection to the abdominal wall with muscular fascia included in the resected tissue
• Enlarged lymph node is removed or normal lymph node is biopsied for metastatic disease
• 2 layer closure

+ Regional Mastectomy

• Regional mastectomy is the removal of ≥ 2 mammary glands and associated lymph nodes
• Regional mastectomy was originally proposed based on the venous and lymphatic drainage of mammary glands
• Mammary glands 1, 2, 3 ± 4 drain into axillary and cranial sternal lymph node
• Mammary glands 3, 4, 5 ± 2 drain into superficial inguinal lymph node

From: Slatter DH (ed): Textbook of Small Animal Surgery (3rd ed).

• superficial inguinal lymph node has efferent drainage to medial iliac lymph node, lumbar trunk, and cisterna chyli
• indications: large mammary masses in adjacent glands
• dissection similar to local mastectomy

+ Unilateral Mastectomy

• Unilateral mastectomy is the removal of 1 entire mammary chain
• Indications: multiple mammary masses involving ≥ 2 ipsilateral mammary glands
• 2 elliptical incisions performed ending cranial to gland 1 and caudal to gland 5 near the vulva
• Soft tissue dissection to the abdominal wall with muscular fascia included in the resected tissue
• Sissection begun at gland 5 as ligation of caudal superficial epigastric reduces hemorrhage
• Allis tissue forceps placed on gland 5 and sharp and blunt dissection used to elevate mammary chain
• Caudal superficial epigastric artery and vein are ligated and divided
• Plane of dissection is less defined at the paracostal arch
• Superficial inguinal lymph node is located in the inguinal fat pad
• Axillary lymph node is located immediately ventral to the latissimus dorsi muscle near the lateral thoracic artery
• 2 layer closure ± penrose drain
• Postoperative management: analgesia for 24 hours and non-adherent bandage and stockingette

+ Staged Bilateral Mastectomy

• Staged procedure: unilateral mastectomy 6 weeks apart
• Advantages: closure easier due to skin stretch and each procedure shorter than bilateral alone
• Staged procedures preferred in breeds with less skin for closure (i.e., Greyhound and Dachshund)
• disadvantage: 2 general anesthetics and surgeries are required

+ Simultaneous Bilateral Mastectomy

• Indications: multiple and bilateral mammary gland involvement in otherwise healthy dogs
• Assess skin pliability before attempting simultaneous procedure by grasping lateral margins and moving them medially towards then ventral midline while in dorsal recumbency
• Dissection similar to unilateral mastectomy except triangular skin over xyphoid is preserved
• Wound closure: walking sutures, intradermal sutures from caudal to cranial, and simple interrupted sutures
• Stent sutures may be required near the xyphoid process where tension is the greatest
• Wound dehiscence is common and tension relieving techniques should be considered
• Postoperative management the same as unilateral mastectomy

+ General Considerations

• poor prognostic factors include:
• tumor size > 3cm
• ulceration
• histologic grade and type
• degree of nuclear differentiation
• lymphoid cellular reactivity in tumor vicinity
• degree of invasion
• intravascular growth
• steroid hormone receptor activity (i.e., no estrogen receptors)
• DNA aneuploidy
• S-phase fraction as measure of cellular proliferation
• AgNOR counts
• metastatic disease to regional lymph nodes and distant sites

+ Tumor Size

• MST is significantly better for tumors < 5 cm (i.e., stage I and II disease) (MST 112 weeks v 40 weeks)
• MST is significantly better for tumors < 3 cm (i.e., stage I disease) (MST 22 months v 14 months)
• Local tumor recurrence rates are significantly better for dogs with tumors < 3 cm at 1-year (30% v 70%) and 2-years (40% v 80%)

+ Clinical Stage

• MST for dogs with stage I disease is significantly better than stage II-IV disease (24 months v 12 months for stage II, 15 months for stage III, and 19 months for stage IV disease)
• MST is dependent on clinical stage:
• MST 500 days for stage I mammary tumors
• MST 420 days for stage II mammary tumors
• MST 210 days for stage III mammary tumors
• MST 90 days for stage IV mammary tumors

+ Histologic Type

• Carcinomas have a better prognosis than sarcomas
• Majority of dogs with mammary sarcomas die from tumor-related causes within 9-12 months
• Carcinoma subtypes have prognostic importance with ductular carcinoma and carcinosarcoma associated with a poorer prognosis
• True carcinomas have a higher metastatic rate (100%) than ADC in mixed mammary tumors (34%)
• Ductular carcinomas have a higher rate of metastasis and mortality
• Mortality rates: 20% lobular ADC, 65% ductular ADC and 15% for other mammary ADC
• MST for anaplastic carcinoma (2.5 months) is significantly decreased compared to ADC (21 months), solid carcinoma (16 months), and other mammary tumors (14 months)
• Carcinosarcoma and inflammatory mammary carcinoma associated with 100% fatality
• MST 25 days for inflammatory mammary carcinoma
• Infiltration of carcinoma into adjacent tissue is associated with a poor prognosis

+ Histologic Grade

• Carcinoma in situ
• Invasion of surrounding stroma without vascular or lymphatic invasion
• Vascular or lymphatic invasion or regional lymph node metastasis
• Distant metastasis
• Histologic grade and degree of differentiation are significantly related to tumor aggressiveness
• 19% of grade 0, 60% of grade 1, and 97% of grade 2 mammary tumors have recurrence or metastasis within 2 years of mastectomy

+ Nuclear Differentiation

• Mammary tumors are further classified based on degree of nuclear differentiation: poor, moderate, and well
• Local tumor recurrence in 24% of grade 1, 68% of grade 2, and 90% of grade 3 mammary carcinomas

+ Lymphoid Cellular Reaction

• Lymphoid cellular reaction in tumor vicinity may represent immunologic antitumor response
• Local tumor recurrence and metastasis is more common in dogs without lymphoid cellular reaction in tumor vicinity
• 45% of grade 1 mammary tumors with lymphoid cellular reactivity have recurrence within 2 years v 83% of grade 1 mammary tumors without lymphoid cellular reactivity

+ Estrogen Receptors

• Presence of estrogen receptors above a certain threshold associated with improved postoperative survival
• However, estrogen receptors are associated with degree of differentiation
• Estrogen expression significantly decreased with increased tumor size, ulceration, lymph node metastasis, and malignant histology, and is inversely correlated with PCNA index

+ Hemostatic Abnormalities

• ≥ 1 hemostatic abnormality in 67% dogs with mammary carcinoma and incidence increases with histologic grade
• Hemostatic abnormalities are more common with metastasis, extensive necrosis, inflammatory carcinoma, fixed tumors, or histologic evidence of penetration of tumor capsule
• Abnormal hemostatic parameters include platelet count, PT, APTT, thrombin time, plasma activity of factors V, VIII and X, plasma concentrations of fibrinogen, fibrin monomers and FDP, and AT-III

+ Ovariohysterectomy

• Effect of ovariohysterectomy on local tumor recurrence and survival is controversial
• Ovariohysterectomy concurrently with mastectomy or within 2 years of mastectomy for dogs with mammary carcinoma significantly increases survival time, with a MST of 755 days v MST 286 days for dogs spayed > 2 years before mastectomy and MST 301 days for intact dogs without concurrent ovariohysterectomy, and increased survival time by 45%
• MST between dogs with mastectomy and dogs with mastectomy and ovariohysterectomy are not statistically different (8 and 10 months compared to 8.4 months)
• However, other studies show ovariohysterectomy does not improve tumor-related or overall survival time in dogs with mammary tumors treated with mastectomy (8.4 months v 8-10 months)

+ Lymph Node Metastasis

• Controversial as not a significant factor in multivariate analysis but is a significant factor in univariate analysis
• Lymph node involvement is associated with significantly DFI (6-month local tumor recurrence rate 80% v 30%) and survival time
• MST is significantly decreased with metastatic disease (5 months v 28 months)

+ Other

• High fraction of cells in the S-phase and DNA aneuploidy is associated with reduced survival times in 136 dogs
• Ki67 labeling index is associated with poor prognosis
• AgNOR counts are associated with cellular proliferation and hence high counts associated with poor prognosis
• Proliferative cell nuclear antigen (PCNA) index is highest in malignant tumors (16%-27%) compared to benign tumors (4.4%-5.3%), mammary hyperplasia (2%), and normal mammary tissue (1%)
• c-erbB-2 over-expression is associated with development of metastatic disease and may be important for development of malignancy
• Telomerase activity is significantly higher in dogs with mammary ADC than benign mammary tumors, but telomerase activity is not present in malignant mammary mixed tumor
• Malignant mammary tumors without progesterone receptors proliferate at a higher rate than malignant tumors with progesterone receptors