PATHOPHYSIOLOGY

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

•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 behaviour

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

CLINICAL SIGNS

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)

DIAGNOSIS

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

Clinical Staging

MEDICAL MANAGEMENT

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

SURGICAL MANAGEMENT

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

•dissection 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

PROGNOSIS

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