Feline Mammary Carcinoma

CHAPTER

59

 

Feline Mammary Carcinoma Beth Overley-Adamson and Jennifer Baez

EPIDEMIOLOGY AND RISK FACTORS Epidemiology

After skin and hematopoietic tumors, mammary tumors are the third most common tumor type in female domestic cats and account for 17% of feline tumors.1-3 The reported incidence is 25.4 per 100,000 female cats per year, although geographical variation is likely because of different neutering and care practices.1,4,5 Mammary tumors are most common in middle-aged to older female cats, with a mean age at diagnosis of 10 to 12 years.1,6,7 Breed has been variably considered as a risk factor for cats. Siamese and domestic shorthair cats are reported to be at increased risk, and Siamese are reported to be significantly younger than other breeds when diagnosed with mammary tumors.3,8,9

Risk Factors The most significant risk factor is exposure to endogenous female hormones, as in other species. Female cats are at significantly increased risk of mammary tumors, and sexually intact cats have a sevenfold higher risk than spayed cats.10-12 Similar to what has been found in dogs, prolonged exposure to ovarian hormones increases risk of mammary tumor development, and ovariohysterectomy (OVH) performed during the first year of a cat’s life significantly reduces its risk. In one study, cats spayed before 6 months of age had 9% risk, and those spayed between 6 and 12 months of age had 14% risk of mammary carcinoma development compared with intact cats.10 Put differently, risk reductions of 91% and 86% were noted in cats that underwent OVH before 6 months and between 6 and 12 months of age, respectively. Minimal to no risk reduction was observed for cats spayed after 1 year of age. Prolonged use of exogenous hormones (e.g., megestrol acetate, medroxyprogesterone acetate) to prevent pregnancy, treat skin diseases, or control aggression has also been implicated in mammary tumor development in cats. Studies have shown that progestins induce changes in mammary gland tissues, with fibroepithelial hyperplasia as the most common glandular change associated with short-term use of these drugs.13,14 In one study, cats treated with progestins had a relative risk of mammary tumor development of 3.4 compared with those that did not receive progestin treatment.12

578

Also, while most mammary tumors occur in female cats, approximately 3% occur in male cats, many of whom have a history of exposure to exogenous progestins.3,13,15 In one study, 36% (eight of 22) male cats had a history of progestin administration.15

RELEVANT ANATOMY Queens have four pairs of mammary glands that include two pairs of thoracic glands and two pairs of abdominal glands.16 Rarely, additional mammary glands may occur in the inguinal region.17 Reports indicate that the thoracic glands drain cranially to the axillary lymph nodes, while the abdominal glands drain caudally to the superficial inguinal lymph nodes.17 However, it is also known that the central glands (the second thoracic and first abdominal glands) occasionally drain bidirectionally, and the thoracic and first pair of abdominal glands may also drain to the cranial sternal lymph node.17,18 These drainage patterns should be considered both for staging and treatment planning (Figure 59-1).

TUMOR BIOLOGY Histopathological Features

Eighty-five to 95% of feline mammary tumors are malignant; however, benign lesions do occur.19 Hyperplastic and dysplastic lesions include fibroepithelial hyperplasia, lobular hyperplasia, and mammary duct ectasia.19,20 Most common in the cat is a hormone-associated condition called fibroepithelial hyperplasia (also called fibroadenomatous change and hypertrophy), which can be induced by exogenous progestin administration in both female and male cats, or by luteal progesterone in pregnant cats.21 In contrast to malignant lesions of the mammary gland, benign lesions—such as fibroepithelial hyperplasia—usually appear in younger, intact cats. Unlike benign and malignant tumors, however, fibroepithelial hyperplasia usually regresses at the end of pregnancy or when progestin use ends.19,20 Other benign lesions of the feline mammary gland include adenoma, ductal adenoma, fibroadenoma, and intraductal papillary adenoma.19 Most malignant feline mammary lesions are simple epithelial tumors, but sarcomas and other nonepithelial tumor types, such as mast cell tumors or lymphoma, arise on

CHAPTER 59  Feline Mammary Carcinoma

Cranial sternal lymph nodes

SI. Lc.

T1

100%

23%

T2

100%

100%

A1

100%

A. Lc.

65%

A2

Figure 59-1:  Drainage Patterns of Mammary Gland Lymphatics in Cats. A. Lc., Axillary lymph center; SI. Lc., superficial inguinal lymph center. (From Raharison F, Sautet J: Lymph drainage of the mammary glands in female cats. J Morphol 267:292-299, 2006.) T, thoracic; A, abdominal

occasion.19,22,23 Most feline mammary carcinomas (FMCs) develop from the luminal epithelium of the ducts and alveoli.19 Mixed tumors involving both luminal and myoepithelial cells are rare.24,25 Feline mammary carcinomas can be of tubulopapillary, solid, cribriform, or anaplastic types.19,24,25 Less common forms include lipid-rich carcinoma, mucinous carcinoma, spindle cell carcinoma, and carcinoma with squamous differentiation.16,19,24,25 Inflammatory mammary carcinoma has been reported but appears much less frequently than in the dog.26

Hormones Risk of mammary tumor development in cats appears to be determined mostly by exposure to female sex hormones, but the precise role these hormones play in tumorigenesis is unknown.27 Across mammalian species, female hormones are necessary for mammary gland development, and it is known that these hormones can act as mitogens that induce proliferation of the ductal epithelium.28,29 Reports from other species have shown that estrogen and its metabolites may have direct genotoxic effects on mammary tissue, and that progesterone increases mammary gland production of growth hormone and growth hormone receptors that have been implicated in mammary tumorigenesis.28-31 It is likely that both hormonal exposure and growth factor pathways play a role in feline mammary tumor development as in other species, but other factors are likely to contribute as well.

Comparative Data Studies have shown that hormone receptor expression is less frequent in FMCs in contrast to canine or human breast cancers.32-35 In human breast cancers, estrogen receptors (ERs) and progesterone receptors (PRs) are expressed in about 70% to 80% of cases, whereas 15% to 20% are negative for both ER and PR.36 In contrast, few FMCs express ERs (7% to 22%) and PRs (approximately 33%).32-34,37 Therefore, comparative studies have focused on the subset of human

579

breast cancers that are hormone-negative. These human hormone-negative tumors are often additionally negative for human epidermal growth factor receptor 2 (HER2) expression. These tumors comprise a particularly aggressive subset of human breast cancers known as triple negative breast cancer (TNBC).38 In addition to hormone receptor evaluation, comparative studies have evaluated HER2 expression in FMCs, and, although results have been highly variable39 among studies, the feline studies that have used the Food and Drug Administration-approved human assay HerceptTest have reported HER2 expression rates similar to those in humans (16% to 17%).38,40 One of these studies reported that 58% of the assessed FMCs were triple negative cancers similar to human TNBC; therefore, FMCs may be a valuable comparative model to evaluate treatment therapies for an aggressive human breast cancer subtype that currently lacks effective targeted therapies.38 Another study tested FMCs for mammalian target of rapamycin (mTOR) overexpression.41 Mammalian target of rapamycin overexpression in human hormone-independent breast cancers, such as TNBC, forms the basis for the development of the mTOR inhibitor rapamycin. The feline study evaluated 58 FMCs and six FMC cell lines by Western blot analysis.41 Results showed that 53% of the feline tumors were triple negative (ER, PR, and HER2 negative), and those that expressed mTOR were more likely to be triple negative samples, which further supports the possibility of feline mammary carcinoma as a useful comparative model for future evaluation of targeted treatments. Finally, it is well known that BRCA1 and BRCA2 mutations can increase the risk of breast cancer in women. BRCA1 and BRCA2 genes produce tumor suppressor proteins involved with DNA repair. Dysfunctional BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers and account for 5% to 10% of breast cancers in humans.42 One study tested FMCs for BRCA1 and BRCA2 mutations but found no mutations or allelic losses in these genes.38 However, the sample size may have been too small.38 Also, BRCA1 and BRCA2 dysfunction could arise through other pathways, such as mutations in different parts of the gene or epigenetic gene silencing.38 More testing will need to be done to clarify the role of BRCA1 and BRCA2 in feline tumors.

CLINICAL DATA History and Presentation

Patient history often includes chronic progestin use, intact reproductive status, or late ovariectomy. Tumors generally arise as round, discrete masses within the mammary glands, and 60% of cats have more than one tumor at presentation.8 The associated nipples may be swollen and may exude clear or tan fluid. Larger tumors may appear inflamed or ulcerated secondary to trauma or from tumor necrosis, although true inflammatory mammary carcinomas are rare in cats.26 Patients may also present with swelling, edema, and discomfort

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secondary to tumor thrombi lodged in the femoral arteries and from decreased venous return from the femoral veins.43 Unfortunately, physical examination findings are not specific for benign or malignant disease; however, nipple association, tumor ulceration, or the presence of enlarged lymph nodes— particularly in an older patient—would lead one to suspect malignancy.

Diagnosis and Staging Diagnosis can be obtained by cytology or biopsy. Because chain mastectomy is usually the recommended surgery for FMCs, malignancy should be established before definitive treatment by incisional biopsy or cytology.43 Staging is imperative for all patients with malignant tumors and most particularly for those with larger tumors (greater than 2 to 3 cm in diameter) or high-grade tumors. The most common sites of metastasis include the regional lymph nodes (axillary, inguinal), lungs, pleura, and liver.44 Staging diagnostics should include a thorough physical examination, complete blood count, serum biochemistries, urinalysis, cytological and/or histological assessment of all masses, lymph node evaluation via palpation and cytology or biopsy, and either three-view thoracic radiographs or thoracic computed tomography (CT) scan. The CT scan is the preferred thoracic staging modality for patients that will undergo extensive surgical treatment because it is a more sensitive test. An abdominal ultrasound is also recommended to assess general health and to check for hepatic, renal, splenic, and nodal metastasis. Feline mammary carcinomas are categorized with a fourstage system based on tumor size, regional lymph node metastasis, and systemic metastasis.19,45 Stage I tumors are less than 2 cm in diameter and have no evidence of tumor spread. Stage II tumors are larger (2 to 3 cm in diameter) and have no evidence of tumor spread. Stage III tumors are tumors with positive regional lymph nodes or tumors of increased size (greater than 3 cm in diameter) regardless of lymph node status. Stage IV tumors have distant metastatic disease and can be of any size or lymph node state (Table 59-1).

PROGNOSTIC FACTORS Clinical Factors

Prognosis is guarded for most cats, and death is usually caused by clinical effects secondary to progression of local disease (disease within the mammary chain) or metastatic spread to vital organs. On average, the time from tumor diagnosis until death is about 10 to 12 months,46 but the prognostic factors outlined earlier can adjust outcome expectations for individual cases. Tumor size has been the most consistent prognostic factor among studies. Patients with stage I FMCs (those with less than 8 cm3 in volume or 2 cm in diameter and no evidence of metastasis) have reported median survival times (MSTs) greater than 2 years with surgery alone.46,47 Cats with FMCs greater than 27 cm3 in volume or 3 cm in diameter have reported MSTs of 4 to 12 months.47-49 Median survival times for cats with 2- to 3-cm diameter tumors are more variable among studies, but one larger study reported the MST as 24 months (Table 59-2).47-49 Lymph node status also affects prognosis, and FMCs with positive regional lymph nodes have significantly worse outcomes.47-50 In one study of 92 cats with FMC, all those with lymph node metastasis (stage III) died within 9 months of diagnosis (Figure 59-2).51 Clinical stage at presentation has also been shown to be prognostic, with median survival times for cats with stage I, II, III, and IV disease reported to be 29, 12.5, 9, and 1 month(s), respectively (see Table 59-2).9

Table 59-2  Prognostic Factors for Feline Mammary Tumors Factor

Details

Tumor size

Diameter <3 cm—MST 21-24 months Diameter >3 cm—MST 4-12 months

Clinical stage

Stage I—MST 29 months Stage II—MST 12.5 months Stage III—MST 9 months Stage IV—MST 1 month

Surgical extent

Radical mastectomy reduces recurrence rate compared with conservative mastectomy or lumpectomy

Histopathological grade

Well-differentiated—100% survival at 1 year postsurgery Poorly differentiated—0% survival at 1 year postsurgery

Mitotic index

<2 mitotic figures per high-power field are associated with longer survival times

Table 59-1  Staging of Feline Mammary Cancers Stage

Tumor Size

Lymph Node Status

Metastasis

Stage I

T1 <2 cm

N0

M0

Stage II

T2 2-3 cm

N0

M0

Stage III

T1 or T2 T3 >3 cm

N1 (positive) N0 or N1

M0 M0

Stage IV

Any

Any

M1

From McNeill CJ, Sorenmo KU, Shofer FS, et al: Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma, J Vet Intern Med 23:123-129, 2009.

MST, median survival time.

CHAPTER 59  Feline Mammary Carcinoma

sion), but these have yet to find utility in routine clinical practice.54-64

1.0 P0.0001 Cumulative survival (percent)

0.8

TREATMENT Surgery

No

0.6

0.4

Yes

0.2

0

581

0

12

24

36

48

Time (months)

Figure 59-2:  Kaplan-Meier Survival Curves According to Lymph Node Status. Queens with lymph node metastasis (positive nodes) on clinical presentation (n = 17, continuous line) showed shorter overall survival time compared with queens with negative nodes (n = 47, dashed line). (From Seixas, F, Palmeira, C, Pires, MA, et al: Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathologic and survival analysis. Vet J. 187:6571, 2011.)

Histological Factors A grading system similar to that used in dogs and humans has been applied to FMCs and has been shown to be prognostic both for survival and disease-free interval (DFI).51-53 Tumor grading is based upon a system that scores for tubule formation, nuclear pleomorphism, and mitotic count. In one study, the death rate at 1 year postsurgery for cats with welldifferentiated mammary carcinoma was 0%, whereas the rate was 100% at 1 year in patients with poorly differentiated tumors (see Table 59-2).52 Another study correlated tumor grade with both DFI and overall survival.51 In that study, the tumor-related death rate at 1 year was 0% for grade 1, 30% for grade 2, and 90% for grade 3 tumors. Progression-free survival rates at 1 year were 100% with grade 1 tumors, 50% with grade 2 tumors, and 6% with grade 3 tumors. Median overall survival for cats with grade 3 tumors was 6 months and 36 months for those with grade 1 tumors; grade correlated strongly with patient age (younger cats had more grade 1 tumors) and tumor size (larger tumors tended to be higher grade).51 Lymphatic invasion, vascular invasion, lymph node metastasis, and mitotic index have all been shown to correlate with survival time.51,52 Several other factors have been evaluated (Ki67, argyrophilic nucleolar organizer region, proliferating cell nuclear antigen, hormone receptors, HER2 overexpression, cyclooxygenase-2 expression, AKT expres-

Surgery should be the primary treatment recommendation for FMCs without distant metastatic disease, and the recommended surgical procedure should be either a unilateral or staged bilateral chain mastectomy depending on the extent of disease.45,47 There is a high rate of locoregional recurrence with more conservative treatment.45 Studies have shown that chain mastectomy significantly improves disease-free survival and reduces the need for recurrent surgeries.47 Although overall survival time has not been shown to be significantly improved with chain mastectomy, overall survival is considered the more subjective metric, because it varies based on the owner’s perception of the patient’s quality of life and on the owner’s willingness to euthanize when the patient is suffering. Both for quality-of-life purposes and according to principles of cancer treatment, given the aggressive nature of this disease and the known lymphatic drainage pathways for FMC, the recommendation for a chain mastectomy makes sense.64 Furthermore, for tumors that are fixed, portions of the body wall and the muscular fascia should be removed in en bloc resections.65 Bilateral chain mastectomy is usually performed in two stages unless the surgeon believes there is adequate tissue to attempt a bilateral chain mastectomy all at once. With these larger surgeries, associated lymph nodes are also removed and should be separately evaluated histologically. Because lymph node involvement significantly changes the prognosis for these cats, efforts should be made to assess the draining lymph nodes via cytology or histopathology. Ultrasound guidance can also be used to identify lymph nodes, and lymph node mapping has been described in the cat.66,67

Systemic Treatment The current literature supports the recommendation that small (less than 2 cm diameter), low-grade tumors with negative staging that are treated with adequate surgery need no adjunctive treatment for long-term survival.45,47 However, standard-of-care treatment recommendations for FMCs have not yet been formulated. Hormonal and targeted therapies that are currently used in human medicine are not commonly used in feline medicine and have not been well evaluated in feline patients, in part because the laboratory testing of FMCs for estrogen receptors, progesterone receptors, or HER2 overexpression is not routine. Also, because it has been recognized that many FMCs are negative for these molecular markers, it is unlikely that the use of these targeted therapies will become common in feline practice. Most treatment studies to date instead have focused on the use of traditional chemotherapeutics.

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Doxorubicin has been the most studied chemotherapy agent for the treatment of FMC. In the macroscopic disease setting for stage III and IV FMCs, doxorubicin-based treatment resulted in objective tumor responses in about 50% of cases reported.53,68,69 These studies have provided the rationale to test doxorubicin-based protocols in the postoperative setting as well, as it would be assumed that the response rate of tumors in the microscopic or adjuvant setting would be as good as or better than that of the macroscopic or gross tumor state. Table 59-3 summarizes prognostic factors, guidelines for systemic therapy based on these factors, and strength of supporting evidence. Unfortunately, studies have yet to show clear benefit from adjunctive treatment. This may be because there is no benefit, but it is more likely that further evaluation is needed to make an accurate determination. Currently, there are no prospective, randomized treatment studies to guide recommendations. One study of 23 cats with stage III or less FMC showed a MST of 460 days with surgery and a protocol that used doxorubicin and meloxicam; however, no control group was used for comparison and so no conclusions can be drawn

about the benefits of one treatment versus the other.70 Another study of 67 cats with stage III or less FMC reported an MST of 448 days; however, this study also lacked a control group. 71 A third report used a contemporaneous control population in a multi-institutional, retrospective study that included 73 cats with stage III or less FMC, and this study found no significant differences in survival between those treated with an adjuvant doxorubicin-based protocol and those that were not.45 However, there was a subgroup of cats treated with chain mastectomy and adjuvant doxorubicinbased chemotherapy that survived significantly longer than those treated with chain mastectomy alone (1998 versus 414 days) (Table 59-4).45 The conclusion reached was that not all FMC patients will benefit from chemotherapy treatment, but certain subsets might. To test this, prospective randomized trials are needed. Although these data can make treatment recommendations confusing at this time, it seems most appropriate to recommend chain mastectomy for local disease control and adjunctive doxorubicin-based treatment for larger tumors, histologically or clinically high-grade tumors, and those with positive lymph nodes.

Table 59-3  Prognostic Factors and Indications for Adjuvant Chemotherapy with Level of Supporting Evidence in Cats with Malignant Mammary Tumors Tumor Size

Lymph Node Involvement

Histopathologic Parameters

Indication for Chemotherapy −(No) or +(Yes)

Evidence Level*

<2 cm/8 cm3

Negative

Carcinoma

− − +†

−1 +3

2-3 cm/8-27 cm3

Negative

Carcinoma

− +†

−3 +3

>3 cm/27 cm3

Negative

Carcinoma

+

1, 2, 3

Any

Positive

Carcinoma

+

2, 3, 5

From Sorenmo KU, Worley DR, Goldschmidt MH: Tumors of the mammary gland. In Withrow and MacEwen’s small animal clinical oncology, ed 5, St Louis, 2013, Elsevier/Saunders, pp 550. *Evidence level 1: prospective randomized trial; level 2: prospective, nonrandomized trial; level 3: retrospective study; level 5: extrapolation from human breast cancer studies. Minus (supports chemotherapy), Plus (against chemotherapy). † Vascular invasion and high grade were found to be independent negative prognostic factors in multivariate analysis.

Table 59-4  Analysis of Effect of Surgery vs Surgery Plus Chemotherapy on Survival Times for Feline Mammary Carcinoma Surgical Procedure

SURGERY + ADJUVANT DOXORUBICINBASED CHEMOTHERAPY

SURGERY ALONE No. of Cats

ST (Days)

95% CI

No. of Cats

ST (Days)

95% CI

P-Value

Local

24

1406

454-NR

16

729

496-NR

0.47

Radical

13

414

203-NR

20

892

616-1998

0.16

Radical unilateral

10

414

266-NR

8

1998

NR

0.03

Radical bilateral

3

NR

67-NR

12

761

476-1751

0.90

From McNeill CJ, Sorenmo KU, Shofer FS, et al: Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma. J Vet Intern Med 23:123-129, 2009. Results shown are median number of days with 95% confidence intervals (CI). P < 0.05 considered statistically significant. NR, median survival time not reached (more than half the cats were censored at study end); ST, survival time.

CHAPTER 59  Feline Mammary Carcinoma

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References 1. Dorn CR, Taylor DO, Frye FL, et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. I. Methodology and description of cases. J Natl Cancer Inst 40:295–305, 1968. 2. Dorn CR, Taylor DO, Schneider R, et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. J Natl Cancer Inst 40:307–318, 1968. 3. Hayes HM, Jr, Milne KL, Mandell CP: Epidemiological features of feline mammary carcinoma. Vet Rec 108:476–479, 1981. 4. Vascellari M, Baioni E, Ru G, et al: Animal tumour registry of two provinces in northern Italy: incidence of spontaneous tumours in dogs and cats. BMC Vet Res 5:39, 2009. 5. Egenvall A, Bonnett BN, Haggstrom J, et al: Morbidity of insured Swedish cats during 1999-2006 by age, breed, sex, and diagnosis. J Feline Med Surg 12:948–959, 2010. 6. Johnston SD, Kustritz MVR, Olson PNS: Disorders of the mammary gland of the queen. In Johnston SD, Kustritz MVR, Olson PNS, editors: Canine and feline theriogenology, Philadelphia, 2001, Saunders, pp 474–485. 7. Kustritz MV: Determining the optimal age for gonadectomy of dogs and cats. J Am Vet Med Assoc 231:1665–1675, 2007. 8. Hayes AA, Mooney S: Feline mammary tumors. Vet Clin North Am Small Anim Pract 15:513–520, 1985. 9. Ito T, Kadosawa T, Mochizuki M, et al: Prognosis of malignant mammary tumor in 53 cats. J Vet Med Sci 58:723–726, 1996. 10. Overley B, Shofer FS, Goldschmidt MH, et al: Association between ovarihysterectomy and feline mammary carcinoma. J Vet Intern Med 19:560–563, 2005. 11. Misdorp W: Progestagens and mammary tumours in dogs and cats. Acta Endocrinol (Copenh) 125(Suppl 1):27–31, 1991. 12. Misdorp W, Romijn A, Hart AA: Feline mammary tumors: a case-control study of hormonal factors. Anticancer Res 11:1793–1797, 1991. 13. Weijer K, Head KW, Misdorp W, et al: Feline malignant mammary tumors. I. Morphology and biology: some comparisons with human and canine mammary carcinomas. J Natl Cancer Inst 49:1697–1704, 1972. 14. Loretti AP, Ilha MR, Ordas J, et al: Clinical, pathological and immunohistochemical study of feline mammary fibroepithelial hyperplasia following a single injection of depot medroxyprogesterone acetate. J Feline Med Surg 7:43– 52, 2005. 15. Skorupski KA, Overley B, Shofer FS, et al: Clinical characteristics of mammary carcinoma in male cats. J Vet Intern Med 19:52–55, 2005. 16. Silver IA: The anatomy of the mammary gland of the dog and cat. J Small Anim Pract 7:689– 696, 1966. 17. Raharison F, Sautet J: Lymph drainage of the mammary glands in female cats. J Morphol 267:292–299, 2006.

18. Raharison F, Sautet J: The topography of the lymph vessels of mammary glands in female cats. Anat Histol Embryol 36:442–452, 2007. 19. Hayden DW, Nielsen SW: Feline mammary tumours. J Small Anim Pract 12:687–698, 1971. 20. Misdorp W, Else R, Hellmen E, et al: Histological classification of mammary tumors of the dog and the cat, Washington, DC, 1999, American Registry of Pathology. 21. Hayden DW, Barnes DM, Johnson KH: Morphologic changes in the mammary gland of megestrol acetate-treated and untreated cats: a retrospective study. Vet Pathol 26:104–113, 1989. 22. Withrow SJ, Vail DM, Page R: Withrow and MacEwen’s small animal clinical oncology (Kindle Location 31795). Elsevier Health Sciences 2013. Kindle Edition. 23. Zappulli V, Caliari D, Rasotto R, et al: Proposed classification of the feline “complex” mammary tumors as ductal and intraductal papillary mammary tumors. Vet Pathol 50:1070–1077, 2013. 24. Seixas F, Palmeira C, Pires MA, et al: Are complex carcinoma of the feline mammary gland and other invasive mammary carcinoma identical tumours? Comparison of clinicopathologic features, DNA ploidy and follow-up. Res Vet Sci 84:428–433, 2008. 25. Seixas F, Pires MA, Lopes CA: Complex carcinomas of the mammary gland in cats: pathological and immunohistochemical features. Vet J 176:210–215, 2008. 26. Perez-Alenza MD, Jimenez A, Nieto AI, et al: First description of feline inflammatory mammary carcinoma: clinicopathological and immunohistochemical characteristics of three cases. Breast Cancer Res 6:R300–R307, 2004. 27. Withrow SJ, Vail DM, Page R: Withrow and MacEwen’s small animal clinical oncology (Kindle Location 31718). Elsevier Health Sciences 2013. Kindle Edition. 28. Russo J, Russo IH: The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 102:89–96, 2006. 29. Okoh V, Deoraj A, Roy D: Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer. Biochim Biophys Acta 1815:115–133, 2011. 30. Mol JA, Lantinga-van Leeuwen IS, van Garderen E, et al: Mammary growth hormone and tumorigenesis—lessons from the dog. Vet Q 21:111–115, 1999. 31. van Garderen E, Schalken JA: Morphogenic and tumorigenic potentials of the mammary growth hormone/growth hormone receptor system. Mol Cell Endocrinol 197:153–165, 2002. 32. Rutteman GR, Blankenstein MA, Minke J, et al: Steroid receptors in mammary tumours of the cat. Acta Endocrinol (Copenh) 125(Suppl 1):32–37, 1991. 33. Millanta F, Calandrella M, Bari G, et al: Comparison of steroid receptor expression in normal, dysplastic, and neoplastic canine and

feline mammary tissues. Res Vet Sci 79:225– 232, 2005. 34. de las Mulas JM, van Niel M, Millán Y, et al: Immunohistochemical analysis of estrogen receptors in feline mammary gland benign and malignant lesions: comparison with biochemical assay. Domest Anim Endocrinol 18:111–125, 2000. 35. Mulas JMD, Van Niel M, Millán Y, et al: Progesterone receptors in normal, dysplastic and tumourous feline mammary glands. Comparison with oestrogen receptors status. Res Vet Sci 72:153–161, 2002. 36. Zafrani B, Aubriot MH, Mouret E, et al: High sensitivity and specificity of immunohistochemistry for the detection of hormone receptors in breast carcinoma: comparison with biochemical determination in a prospective study of 793 cases. Histopathology 37:536–545, 2000. 37. Hamilton JM, Else RW, Forshaw P: Oestrogen receptors in feline mammary carcinoma. Vet Rec 99:477–479, 1976. 38. Wiese DA, Thaiwong T, Yuzbasiyan-Gurkan V, et al: Feline mammary basal-like adenocarcinoma: a potential model for human triplenegative breast cancer (TNBC) with basal-like subtype. BMC Cancer 13:403, 2013. 39. Rasotto R, Caliari D, Castagnaro M, et al: An immunohistochemical study of HER-2 expression in feline mammary tumours. J Comp Pathol 144:170–179, 2011. 40. Ordas J, Millan Y, Dios R, et al: Protooncogene HER2 in normal, dysplastic and tumorous feline mammary glands: an immunohistochemical and chromogenic in situ hybridization study. BMC Cancer 7:179–184, 2007. 41. Maniscalco L, Millan Y, Lussich S, et al: Activation of mammalian target of rapamycin (mTOR) in triple negative feline mammary carcinomas. BMC Vet Res 9:80, 2013. 42. Campeau PM, Foulkes WD, Tischkowitz MD: Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet 124:31–42, 2008. 43. Giménez F, Hecht S, Craig LE, et al: Early detection, aggressive therapy: optimizing the management of feline mammary masses. J Feline Med Surg 12:214–224, 2010. 44. Hahn KA, Adams WH: Feline mammary neoplasia: biological behavior, diagnosis, and treatment alternatives. Feline Pract 25:5–11, 1997. 45. McNeill CJ, Sorenmo KU, Shofer FS, et al: Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma. J Vet Intern Med 23:123– 129, 2009. 46. Lana SE, Rutteman GR, Withrow SJ: Tumors of the mammary gland. In Withrow SJ, Vail DM, editors: Small animal clinical oncology, St Louis, 2007, Elsevier, pp 619–636. 47. MacEwen EG, Hayes AA, Harvey HJ, et al: Prognostic factors for feline mammary tumors. J Am Vet Med Assoc 185:201–204, 1984. 48. Ito T, Kadosawa T, Mochizuki M, et al: Prognosis of malignant mammary tumor in 53 cats. J Vet Med Sci 58:723–726, 1996.

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Oncology

49. Viste JR, Myers SL, Singh B, et al: Feline mammary adenocarcinoma: tumor size as a prognostic indicator. Can Vet J 43:33–37, 2002. 50. Weijer K, Hart AA: Prognostic factors in feline mammary carcinoma. J Natl Cancer Inst 70:709–710, 1983. 51. Seixas F, Palmeira C, Pires MA, et al: Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J 187:65–71, 2011. 52. Castagnaro M, Casalone C, Bozzetta E, et al: Tumour grading and the one-year postsurgical prognosis in feline mammary carcinomas. J Comp Pathol 119:263–275, 1998. 53. Jeglum KA, deGuzman E, Young KM: Chemotherapy of advanced mammary adenocarcinoma in 14 cats. J Am Vet Med Assoc 187:157–160, 1985. 54. Millanta F, Lazzeri G, Mazzei M, et al: MIB-1 labeling index in feline dysplastic and neoplastic mammary lesions and its relationship with postsurgical prognosis. Vet Pathol 39:120–126, 2002. 55. Birner P, Oberhuber G, Stani J, et al, Austrian Breast & Colorectal Cancer Study Group: Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER2 protein expression in breast cancer. Clin Cancer Res 7:1669–1675, 2001. 56. Preziosi R, Sarli G, Benazzi C, et al: Multiparametric survival analysis of histological stage and proliferative activity in feline mammary carcinomas. Res Vet Sci 73:53–60, 2002. 57. Dias Pereira P, Carvalheira J, Gartner F: Cell proliferation in feline normal, hyperplastic and neoplastic mammary tissue—an immunohistochemical study. Vet J 168:180–185, 2004.

58. Castagnaro M, Casalone C, Ru G, et al: Argyrophilic nucleolar organiser regions (AgNORs) count as indicator of post-surgical prognosis in feline mammary carcinomas. Res Vet Sci 64:97–100, 1998. 59. Millanta F, Calandrella M, Citi S, et al: Overexpression of HER-2 in feline invasive mammary carcinomas: an immunohistochemical survey and evaluation of its prognostic potential. Vet Pathol 42:30–34, 2005. 60. Millanta F, Citi S, Della Santa D, et al: COX-2 expression in canine and feline invasive mammary carcinomas: correlation with clinicopathological features and prognostic molecular markers. Breast Cancer Res Treat 98:115–120, 2006. 61. Millanta F, Silvestri G, Vaselli C, et al: The role of vascular endothelial growth factor and its receptor Flk-1/KDR in promoting tumour angiogenesis in feline and canine mammary carcinomas: a preliminary study of autocrine and paracrine loops. Res Vet Sci 81:350–357, 2006. 62. Maniscalco L, Iussich S, de las Mulas JM, et al: Activation of AKT in feline mammary carcinoma: a new prognostic factor for feline mammary tumours. Vet J Med 25:297–302, 2011. 63. Preziosi R, Sarli G, Benazzi C, et al: Detection of proliferating cell nuclear antigen (PCNA) in canine and feline mammary tumours. J Comp Pathol 113:301–313, 1995. 64. Morris J: Mammary tumors in the cat: size matters, so early intervention saves lives. J Feline Med Surg 15:391, 2013. 65. Withrow SJ, Vail DM, Page R: Withrow and MacEwen’s small animal clinical oncology

(Kindle Locations 31857-31858). Elsevier Health Sciences 2013. Kindle Edition. 66. Wong JH, Cagle LA, Morton DL: Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 214:637–641, 1991. 67. Patsikas MN, Papadopoulou PL, Charitanti A, et al: Computed tomography and radiographic indirect lymphography for visualization of mammary lymphatic vessels and the sentinel lymph node in normal cats. Vet Radiol Ultrasound 51:299–304, 2010. 68. Mauldin GN, Matus RE, Patnaik AK, et al: Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats. J Vet Intern Med 2:60–65, 1988. 69. Stolwijk JA, Minke JM, Rutteman GR, et al: Feline mammary carcinomas as a model for human breast cancer. II. Comparison of in vivo and in vitro adriamycin sensitivity. Anticancer Res 9:1045–1048, 1989. 70. Borrego JF, Cartagena JC, Engel J: Treatment of feline mammary tumours using chemotherapy, surgery and a COX-2 inhibitor drug (meloxicam): a retrospective study of 23 cases (2002-2007). Vet Comp Oncol 7:213–221, 2009. 71. Novosad CA, Bergman PJ, O’Brien M, et al: Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adenocarcinoma: 67 cases. J Am Anim Hosp Assoc 42:110–120, 2006.