Veterinary Society of
Surgical Oncology

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

MAMMARY TUMORS

T0

No evidence of neoplasia

T1

Tumor < 3 cm in diameter

Primary Tumor

T2

Tumor 3-5 cm in diameter

T3

Tumor > 5 cm in diameter

N0

No evidence of lymph node involvement

N1

Regional lymph node involvement

Node

M0

No evidence of metastasis

M1

Evidence of distant metastasis with site specified

Metastasis

Clinical Stage

I

II

III

T

T1

T2

T3

N

N0

N0

N0

M

M0

M0

M0

IV

T1-3

N1

M0

V

T1-3

N0-1

M1

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