Canine Mammary Carcinoma

An 8-year-old female spayed Golden Retriever initially presented to her primary veterinarian for surgical resection of a subcutaneous mass suspected to be associated with the left 2nd mammary gland.  It was unknown how long the mass had been present and the rate of growth.  The mass was bilobed on palpation and reported to be freely moveable.  The mass was removed using a CO2 laser and a Penrose drain was placed.  Rimadyl was prescribed and all resected tissue was submitted for histopathology, which revealed adenocarcinoma with vascular invasion and extension to the margins.  There were on average 2 mitotic figures/HPF.  Anisocytosis and anisokaryosis were moderate to marked and there was individual cell necrosis and focal necrosis noted.  The tumor was poorly differentiated but it was suspected that it might be mammary in origin.  Referral to an oncologist was recommended for further evaluation and treatment.

The patient presented to the oncology service at Hope Veterinary Specialists approximately 2 weeks post surgery.  Blood work performed at that time was unremarkable.  Three view thoracic radiographs were performed which did not reveal any evidence of metastatic disease.  Four treatment options were discussed including a revision surgery followed by chemotherapy vs. chemotherapy alone vs. no further therapy or only low dose therapy.  Due to the incomplete margins and the aggressive appearance on histopathology (high growth rate and vascular invasion) surgical reexcision to remove the scar and residual neoplasia followed by chemotherapy was the recommended treatment of chose.  The chemotherapy protocol discussed was Adriamycin IV q 3 weeks x 4-5 cycles with a CBC postop 1-week Adriamycin administration.

The owner scheduled an appointment with the surgery service a week later.  On physical examination an 8 cm scar coursing from cranial to caudal centered over the left 2nd mammary gland was noted with the previous drain exit site noted ventral and caudal to the scar.  Scar resection with margins laterally and deep including margins around the drain exit site were discussed, as were possible complications and postoperative care.  Surgery was performed the same day and the patient was discharged to the owner the following day.  Postoperatively the patient did well.  The histopathology revealed residual mammary adenocarcinoma with complete excision.  There was greater than 5 mm lateral margins and greater than 5 mm deep margins with the sections examined having a layer of skeletal muscle deep to the site.

Postoperatively the patient did well.  The incision was healed at the 2 week postoperative examination and the skin sutures were removed.  She has completed her Adriamycin based protocol and is currently receiving an NSAID as a maintenance therapy for putative anticancer effects. All restaging visits have been clear and she is currently 9 months from diagnosis.

Mammary tumors occur in both dogs and cats, however, the incidence is higher in dogs than any other species. They are the most third most common tumor in cats and account for 17% of all tumors in female cats. In dogs, half of the mammary tumors are considered malignant, and half of these have metastasized at the time of diagnosis. In contrast, nearly 90% of mammary tumors in cats are malignant.

In dogs, intact females have a seven-fold increased risk of developing mammary cancer compared to neutered females and the age at which ovariohysterectomy is performed is proportional to the risk of developing mammary cancer. The greatest reduction in risk occurs when an OVH is performed prior to the first heat cycle, however a protective exists still exists if performed prior to 2.5 years of age.

Obesity may be a factor in mammary neoplasia in dogs. In cats, exogenous progestins and the combination of estrogen-progestins are associated with a 3-fold risk of developing either benign or malignant mammary tumors. Benign fibroepithelial hyperplasia may also be caused by administration of sex steroids.

It has been shown that roughly half of canine mammary tumors are malignant and half are benign.  A FNA is not always diagnostic and therefore histopathology needs to be submitted to reveal if it is benign or malignant.  Benign mammary tumors include adenoma, benign mixed tumor and papilloma with the simple/complex fibroadenoma being the most common. Malignant tumors include carcinoma, adenocarcinoma, sarcoma, carcinosarcoma and inflammatory carcinoma with carcinomas being the most common.

Typical clinical presentation involves a lump or mass being reported on or near the mammary gland or the nipple itself .  Approximately 2/3rds  to 3/4ths of the tumors occur along the 4th and 5th glands.  Signs that are often associated with malignancy include rapid growth, ill-defined borders of the tumor, fixation to the underlying tissue and ulceration of the tumor.

Staging for mammary tumors involves blood work (CBC, serum chemistry), thoracic radiographs, abdominal ultrasound (if caudal glands), and aspiration of nearby lymph nodes if possible. Pending staging results,  surgery is normally the first recommended treatment of choice.  Surgery can be  performed to remove the mass, the gland itself or the entire chain. Studies have shown no difference in overall survival when comparing removal of the gland itself vs. the entire chain. At the time of surgery, if possible, removal of the draining lymph node is recommended to look for metastasis.

Based upon histopathology and staging results, there are several factor that are prognostic.  These include:

Good

Tumor < 3 cm
Well-circumscribed
Lymph node negative
Lymphoid infiltration
Estrogen/progesterone receptor –
Carcinoma
(Well differentiated)
Proliferation indices-low
Nonulcerated
No lymphatic invasion
No vascular invasions
Low vascularity
Spay within 2 yrs of age
Poor

Tumor >3 cm
Invasive
Lymph node positive
No infiltration
Estrogen/Progesterone 
receptor +
Sarcoma
(poorly differentiated anaplastic)
Proliferation indices-High
Ulcerated
Lymphatic invasion
Vascular invasion
High vascularity
Spay greater than 2 y of age

Based on these factors, it has been found that if dogs have mostly good prognostic indicator they may have a very good quality of life and an overall median survival of >2 years depending upon the case.

In dogs, the extent of surgery does not influence either survival or disease-free interval . The histologic completeness of surgical margins is prognostic for survival so the most aggressive surgery needed to achieve complete margins is recommended.

Chemotherapy is recommended for dogs and cats with malignant and metastatic mammary tumors. The role of chemotherapy is still unknown, despite understanding the poor outcome associated with this disease and the high incidence of metastatic disease. Drugs commonly used in protocols include 5-fluorouracil+cyclophosphamide, doxorubicin alone or with cyclophosphamide, carboplatin, mitoxantrone, paclitaxel and docetaxel. The parent compound Paclitaxel is from the Taxane group of chemotherapy agents with efficacy against breast, lung and ovarian cancer in human oncology. Use in veterinary medicine is limited as a result side effects associated with its excipient Cremophor® EL. Oasmia Pharmaceutical AB has managed to produce a water soluble formulation of Paclitaxel (Paccal® Vet), that does not require premedication and abolish Cremophor® EL related side effects. A Phase I/II study on multiple types of cancers and showed an overall response rate of 74 % with responses noted in patients with mammary carcinoma, squamous cell carcinoma and mast cell tumor. The FDA has given Conditional Approval (CA) for use in patients with nonresectable stage III, IV, or V mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy; and resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy. Two trials are ongoing further evaluating Paccal Vet-CA1 in a larger number of dogs with mammary and squamous cell carcinoma.

Responses of nonresectable mammary tumors to metronomic therapy and tyrosine kinase inhibitors has been reported, however, data is lacking.

Nonsteroidal medications such as Feldene, Deramaxx or Metacam, have been shown to have anticancer effects against mammary tumors and Omega-III fatty acids have been shown to also have anticancer effects and can decrease the risk of these tumors (in people).

Submitted by Lauren May VMD, DACVS

References:

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http://jnci.oxfordjournals.org/content/43/6/1249.short

Sorenmo, K. U., Shofer, F. S., and Goldschmidt, M. H. Effect of spaying and timing of spaying on survival of dogs with mammary carcinoma. J. Vet Intern Med 14, 266-270. 2000.
http://onlinelibrary.wiley.com/doi/10.1111/j.1939-1676.2000.tb01165.x/abstract

Yamagami T, Kobayashi T, Takahashi K, Sugiyama M. Influence of ovariectomy at the time of mastectomy on the prognosis for canine malignant mammary tumors. J Small Anim Pract 1996; 37:462-464.
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Sonnenschein EG, Glickman LT, Goldschmidt MH, McKee LJ. Body conformation, diet, and risk of breast cancer in pet dogs: A case-control study. Am J Epidemiol 1991; 133:694-703.
http://aje.oxfordjournals.org/content/133/7/694.short

Philibert JC, Snyder PW, Glickman N, Glickman LT, Knapp DW, Waters DJ. Influence of host factors on survival in dogs with malignant mammary gland tumors. J Vet Intern Med 2003; 17:102-106.
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Yamagami T, Kobayashi T, Takahashi K, Sugiyama M. Prognosis for canine malignant mammary tumors based on TNM and histologic classification. J Vet Med Sci 1996; 58:1079-1083.
http://jlc.jst.go.jp/DN/JALC/00083270093?from=Google

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Figures 1,2. Histopathological images showing residual carcinoma surrounded by a fibroblastic response and adjacent cross section through suture material. Images and description courtesy of Dr. Danielle  Reel, DVM, Diplomate ACVP, KDL VetPath.

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