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Abstract

Practical relevance:

Mammary tumours are among the most common neoplasms in both cats and dogs, but the prevalence of malignant histological types is far higher in cats (ratio of malignant:benign is at least 4:1).

Clinical challenges:

The more aggressive nature of mammary neoplasia in cats poses challenges for management. Prognosis is affected by tumour size and, therefore, early recognition and treatment of mammary tumours is paramount. Although the primary tumour can be excised surgically, no studies have shown that chemotherapy significantly extends survival time; hence, metastatic spread remains an important clinical problem.

Patient group:

Mammary tumours usually affect older female cats, mainly entire females. Siamese and Oriental breeds may be predisposed. Male cats can develop mammary neoplasia, but this is rare.

Evidence base:

This review summarises the current literature relating to aetiology, pathology, presentation, diagnosis, staging, treatment and prognosis of feline mammary tumours.

Epidemiology

Mammary neoplasia is the third most common tumour type affecting female cats after lymphoma and skin tumours, accounting for 17% of tumours.¹ Reported incidence is 25.4 per 100,000 female cats per year.¹ Although precise statistics are not available, the incidence of mammary tumours may vary globally depending on cultural acceptance of neutering policies. Neutering is less common in Scandinavia and some other parts of Europe than in the UK, for example.

Aetiology

As in humans and dogs, hormonal fluctuations associated with repeated oestrous cycles may influence the development of mammary tumours in cats. This is supported by a case control study reporting that cats spayed before 1 year of age had a decreased risk of developing mammary cancer,⁹ and that intact cats were seven times overrepresented in a population of cats with mammary tumours compared with a control group.¹⁰ However, cats spayed at less than a year old do still develop mammary tumours so the effect of early neutering does not eliminate the risk of mammary tumours,⁸ and early studies reporting more tumours in intact cats may possibly have reflected neutering practices at the time rather than a true increased risk.¹¹

Other evidence to support a hormonal aetiology is that oestrogen and progesterone receptors are found in normal mammary tissues and benign tumours but are often lost in malignant tumours and metastases.^12–17 In addition, exogenous progesterone administration to prevent pregnancy, or for behavioural aggression, causes tumour development (benign and malignant) in both male¹⁸ and female cats.¹⁹ A possible dose-related effect may occur, with increased risk of mam-mary carcinoma if given regularly rather than intermittently.¹⁰

There is no definitive evidence for a viral aetiology for mammary tumours in cats, although this was proposed in early literature, and obesity has not been implicated, unlike in dogs.

Presentation

Cats have four pairs of mammary glands (two thoracic and two abdominal) and, although any gland may be affected, some studies have reported a predisposition for mammary tumours in the caudal glands.^11,20 Mammary tumours present as a single subcutaneous nodule or mass within the mam-mary glands (Figures 1 and 2), which may be discrete and mobile, or attached to underlying tissues and possibly ulcerated in appearance (Figure 3). A few may appear cystic. It is difficult to distinguish benign from malignant nodules in cats, so all should be treated as potentially malignant. Multiple mammary masses within several glands are common (usually ipsilateral but occasionally bilateral) (Figure 4) and were reported in 60% of cats in one study.⁸ Sometimes, the true extent of the disease cannot be appreciated without clipping the fur. Drainage lymph nodes (inguinal or axillary) may also be visibly or palpably enlarged.

Figure 1

Mammary mass in the thoracic glands of an 11-year-old female entire (FE) domestic shorthair (DSH) cat

Figure 2

Mammary mass in the thoracic glands and axillary lymph node of an 8-year-old FE DSH cat

Figure 3

Ulcerated mammary mass in the second abdominal gland of a 21-year-old male neutered DSH cat

Figure 4

Bilateral mammary masses before (a) and after (b) clipping

In particularly aggressive inflammatory carcinomas with extensive lymphatic involvement, the glands may be swollen, hot and painful.⁴ This presentation may be difficult to differentiate from fibroadenomatous hyper-plasia (fibroepithelial hypertrophy, feline mam-mary hypertrophy), although the latter more commonly affects young cats.²¹

Diagnosis

If a mammary mass is palpated, confirmation that it is neoplastic requires biopsy of tissue or a fine needle aspirate (FNA) for cytology. Since most feline mammary tumours are malignant, FNAs are more reliable than in dogs and are useful to confirm the diagnosis (Figure 5).

Figure 5

Cytology of feline mammary carcinoma, showing a raft of polygonal neoplastic epithelial cells with anisocytosis and anisokaryosis, some multinucleate cells and prominent nucleoli, often several per nucleus. Courtesy of Elizabeth Villiers

Most feline mammary tumours derive from glandular epithelium and all strictly are adenomas or adenocarcinomas, although the latter are often loosely referred to as carcinomas. Benign tumours are uncommon but, of these, fibroadenoma is most frequently reported, with simple adenoma or duct papilloma rarely seen. The main histological type of mammary tumour in the cat is simple adenocarcinoma derived from the luminal epithelium of the mammary ducts and alveoli (Figure 6). Complex or mixed tumours involving both luminal and myoepithelial cells are extremely infrequent in cats compared with dogs, although they may be associated with a better prognosis.^22,23 In cats, carcinomas may be tubulopapillary, solid, cribriform or mucinous, although squamous cell carcinoma and mixed carcinosarcoma are also reported.²⁴

Figure 6

Histology of feline mammary simple adenocarcinoma. Low power views showing primary tumour invading muscle (a), and pulmonary metastasis (b) with tumour cells in blood vessels and lung tissue. Courtesy of Tim Scase

Inflammatory mammary carcinoma, which has a particularly poor prognosis owing to an additional inflammatory component blocking the lymphatics and affecting lymph drainage and causing swollen, painful glands, has been reported in three cats with underlying highly malignant, papillary mammary carcinomas.²⁵

Staging

If a mammary tumour is suspected or confirmed, investigations should be carried out to determine the local extent and degree of spread throughout the body prior to surgical excision. As so few mammary masses are benign, and gross appearance alone is an unreliable basis on which to distinguish benign from malignant tumours, complete staging should be routine for all mammary masses. The WHO staging system is usually applied (Table 1);²⁶ however, with many tumours being noticed earlier and in less advanced stages, fewer larger tumours over 5 cm diameter are being reported. Measurement of the primary tumour with calipers is important since the size of the tumour influences the prognosis: those <3 cm diameter being associated with better survival rates than those >3 cm (see later).

Table 1

TNM and clinical staging system for feline mammary tumours

Clinical stage	Tumour diameter (T)	Regional lymph node (N)	Distant metastasis (M)
I	<2 cm (T₁)	Negative (N₀)	Negative (M₀)
II	2–3 cm (T₂)	Negative (N₀)	Negative (M₀)
III	>3 cm (T₃) ≤3 cm (T₁–T₂)	Negative or positive (N₀ or N₁) Positive (N₁)	Negative (M₀) Negative (M₀)
IV	Any T	Any N	Positive (M₁)

Adapted from Owen²⁶

Staging of confirmed tumours should include palpation and aspiration of local drainage lymph nodes, since more than a quarter of cats have regional metastasis at the time of diagnosis.²⁷ Involvement of multiple axillary lymph nodes is commonly detected by lymph angiography (58–75% cases) but a single inguinal lymph node predominates (84–94% cats).²⁸ Although the axillary and inguinal lymph nodes are those mainly reported as being affected in feline mammary neoplasia (80% cats), the sternal lymph node may also be involved (30% cats).²⁷

For more distant spread, three-view chest radiography (preferably performed under anaesthesia with inflated lungs) and abdominal ultrasonography should be carried out, since the most common sites of metastasis are the lungs, medial iliac lymph nodes and abdominal organs (Figure 7). Pulmonary metastases usually appear as a miliary pattern on thoracic radiographs, but pleural surfaces can also be affected and in some cases metastatic lung disease can cause pleural effusion (Figure 8). More uncommonly, metastasis to bone can be detected.

Figure 7

Enlarged left medial iliac lymph node chain with surrounding hyperechoic fat detected by abdominal ultrasound at routine staging of an 11-year-old female neutered (FN) Abyssinian with mammary carcinomas of the left caudal abdominal and right cranial thoracic glands

Figure 8

Left lateral (a) and dorsoventral (b) radiographs of the thorax of the cat imaged in Figure 7. These views show general increased opacity within the thoracic cavity, with severe retraction of the lung fields from the dorsal wall and effacement of the cardiac silhouette and diaphragm, consistent with pleural effusion

Advanced imaging (ie, computed tomography [CT]) of the lungs provides more accurate assessment of metastases (see ‘case notes’), and should be used where there is any concern about the radiographic appearance of the lungs (Figure 9).

Figure 9

Left lateral radiograph (a) of a 12-year-old FN DSH cat with a mammary carcinoma of the second abdominal gland. A couple of faint, ill-defined soft tissue opacities superimposed on the cardiac silhouette, and suspicious for metastasis, were noted on this view (arrows) but not the right lateral view. CT of the chest confirmed the presence of a 2–3 mm hyperattenuating nodule in the middle right lung lobe and (b) a 4.8 mm hyperattenuating nodule in the caudal part of the left lung lobe (arrow)

Since most affected cats are elderly, haematology, biochemistry and urinalysis should also be performed to assess for concurrent disease. Paraneoplastic conditions are rarely reported with mammary tumours, and feline leukaemia virus and feline immunodeficiency virus are not impli cated in the aetiology. However, if further treatment, including chemotherapy is being considered, it is important to evaluate viral status since viral immunosuppression may influence whether treatment goes ahead.

Surgical treatment

The mainstay of treatment for mammary tumours is still surgical resection. The extent of surgery is influenced by the lymphatic drainage in the feline mammary gland (see box), as tumour cells spread readily beyond the primary site and complete excision should encompass all known drainage pathways.

Recommended approach

The recommendation based on drainage studies is to perform unilateral or bilateral mamma-ry strips because of possible contact between individual glands and between left and right sides. While radiological imaging studies would suggest that this may not be necessary in every case, additional prognostic analyses do support the use of unilateral or bilateral mam-mary strips since the extent of surgery appears to make a significant difference to local recurrence/disease-free interval (DFI)³³ and survival time.³⁴ For bilateral strips a 2-week interval is recommended between surgeries although simultaneous bilateral mastectomy can also be performed (Figure 10). Tumour fixation to skin or abdominal fascia necessitates removal of these structures en bloc.³⁵

Figure 10

Bilateral mammary strip in a cat with mammary carcinoma. Courtesy of Kathryn Pratschke

Excision of lymph nodes The inguinal lymph node is embedded in the caudal mammary gland and is therefore removed along with the gland as part of a mammary strip. The axillary lymph node should be removed if enlarged or positive for tumour spread on FNA or biopsy, but there is no evidence that prophylactic removal extends survival.

Concurrent ovariohysterectomy There is no evidence that ovariohysterectomy at the time of mastectomy has any benefit on survival or tumour recurrence,⁸ or effect on development of new tumours or carcinoma progression.¹⁰ It might, however, reduce the need for progestin therapy, which may be beneficial.

Chemotherapy

There is some data to show that chemo therapy may be effective on mammary cell lines in vitro,^36–38 and that treatment of non-resectable disease in vivo with doxorubicin and cyclophosphamide may shrink tumour size in 50% cases and possibly increase survival (Table 2).^38–40 The benefit of using chemotherapy as an adjunct to surgical excision of mammary tumours in cats, however, is still not clear (Table 3).

Table 2

Effect of chemotherapy (doxorubicin) on mammary carcinomas (gross disease)

Clinical stage	Number of cats	Treatment	Control group	Median survival (days)	Response	Reference
III or above	14	Doxorubicin (30 mg/m² IV q2 weeks)	No	215 (30.8 weeks)	>50% response in 9/14	Stolwijk et al³⁸
III or above	14	Doxorubicin (20–30 mg/m² IV q3 weeks) + cyclophosphamide (100 mg/m² PO for 3 days q3 weeks)	No	180	>50% response in 5/14	Jeglum et al³⁹
III or above	14	Doxorubicin (25 mg/m² IV) + cyclophosphamide (50 mg/m² PO for 4 days q3 weeks)	No	90	>50% response in 7/14	Mauldin et al⁴⁰

Table 3

Effect of chemotherapy (doxorubicin) as an adjunct to surgical removal of mammary tumours

Clinical stage	Number of cats	Treatment	Control group	Median survival (days)	Median DFI (days)	Reference
III or below	67	Surgery + doxorubicin*	Historical	448	255	Novosad et al⁴¹
III or below	37 36	Surgery alone Surgery + doxorubicin† + cyclophosphamide‡	Surgery alone	1406 848	372 676	McNeill et al³⁴
III or below	23	Surgery + doxorubicin§ + meloxicam¶	Historical	460	269	Borrego et al⁴²

DFI = disease-free interval

Doxorubicin 1 mg/kg IV q3 weeks

†

Doxorubicin dose not given (four cases doxorubicin alone)

‡

Cyclophosphamide dose not given

Doxorubicin 1 mg/kg IV q3 weeks (one case had vincristine 0.7 mg/m² IV and 13 cases had cyclophosphamide 250 mg/m² IV, 1 week after doxorubicin)

Meloxicam 0.2 mg/kg PO on day of surgery, then 0.1 mg/kg q24h for 5 days, then 0.025 mg/kg

A large, multicentre study of 67 cats receiving adjunctive doxorubicin reported a median survival time of 448 days.⁴¹ Although there was no control group in the study, this survival time was deemed longer than historical controls and was similar to that in another study of 23 cats without a control group (460 days) combining adjunctive doxorubicin with the COX-2 inhibitor meloxicam.⁴² A further study of 73 cats, which included a control group of 36 cats undergoing surgical excision only, reported increased survival time and DFI for the cats receiving postoperative doxorubicin and cyclophosphamide (1406 versus 848 days [survival time] and 676 versus 372 days [DFI]);³⁴ however, the difference was not statistically significant.

It is possible that with greater numbers and more statistical power, a true benefit of aggressive chemotherapy may become apparent. Alternatively, a different approach with anti angiogenic metronomic (low dose) chemotherapy may prove effective, although low dose chemotherapy using vincristine, cyclophosphamide and methotrexate did not prevent recurrence or metastasis in one report.⁸

Other therapies

Although immunomodulators such as bacillus calmette-Guerin (BCG),⁴³ Corynebacterium parvum,⁴⁴ liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE)⁴⁵ and oral levamisole⁴⁶ have been tried as intratumoural injections (BCG) or adjuncts to surgical excision of feline mammary tumours, none have proved successful in extending survival time or altering recurrence rate. There are no reports of using antioestrogens such as tamoxifen in cats, probably since most malignant feline mam-mary tumours lack oestrogen receptors and expected benefits would, therefore, appear to be minimal.

The small molecule inhibitors that target receptor tyrosine kinases (receptor tyrosine kinase inhibitors or RTKIs) are effective in the management of some types of veterinary cancers, particularly those with altered TK activity.⁴⁷ Imatinib and masitinib are well tolerated in cats;^48–51 however, there is no information about their efficacy against feline mammary tumours. (Further discussion on the use of targeted therapies in cats, with a particular focus on the idiosyncracies of feline patients, is provided in an accompanying article in this special issue.)

Prognosis

Prognosis is guarded for most cats with mammary tumours, with deaths mainly attributable to local recurrence or metastasis. The average time between detection and death is reported to be 10–12 months;^20,35 however, as already mentioned, several factors affect prognosis of feline mammary tumours (Table 4).

Table 4

Prognostic factors for feline mammary tumours

Factor	Details
Tumour size*	Diameter <3 cm – median survival 21–24 months Diameter >3 cm – median survival 4–12 months
Clinical stage†	Stage I – median survival 29 months Stage II – median survival 12.5 months Stage III – median survival 9 months Stage IV – median survival 1 month
Surgical extent	Radical surgery (mammary strip) reduces recurrence rate compared with more conservative mastectomy
Histopathological grade	Well differentiated – 100% survival at 1 year after surgery Poorly differentiated – 0% survival at 1 year after surgery
Mitotic index	<2 mitotic figures per high power field give longer survival

MacEwen et al³³ and Viste et al.⁵² †Ito et al⁵³

Clinical parameters

Prognosis is very much related to the size of the tumour at initial presentation, with tumours of large volume (>27 cm³) or diameter (>3 cm) being associated with shorter survival times (4–12 months).^8,52,53 The degree of spread at initial presentation (eg, regional lymph node metastasis) also dramatically affects prognosis,^20,33,53 as does the extent of surgery carried out. Radical mastectomy produces a significantly longer DFI,^33,53 and histological completeness of resection correlates with survival.²⁷ The cat’s age may also influence prognosis,^27,33 although more recent studies dispute this.⁵³

Histological parameters

A wealth of literature exists on histological markers detected by pathologists,⁵⁴ some of which influence prognosis. However, few are routinely used in diagnostic laboratories to offer helpful information to clinicians.

The most useful assessment by pathologists is histological grading, which is significantly related to both overall survival and DFI in univariate and multivariate analyses.^55–57 Mitotic index also correlates with survival time,⁵⁸ but although other proliferation markers such as Ki67,^57,59 AgNOR⁶⁰ and PCNA⁶¹ may help determine high histological grade, they have not been shown to be independent prognostic markers. Similarly, although expression of hormone receptors (ER and PR) has been examined in feline carcinomas, receptor status does not correlate with overall survival and is not routinely assessed.^14,15 The epidermal growth factor receptor 2 (Her2/neu) is variably over-expressed in feline carcinomas and, while one study has associated this with survival,⁶² more recent data has not.⁶³ High COX-2 expression in mammary carcinomas has also been linked with poor prognosis,⁶⁴ but this association is complicated by the fact that it also correlates with expression of the angiogenic factor vascular endothelial growth factor (VEGF), which itself is significantly correlated with overall survival.⁶⁵ More recently, expression of the cytoplasmic protein kinase, AKT, which is activated by numerous receptor tyrosine kinases such as EGF or by loss of the tumour suppressor gene PTEN (phosphatase and tensin homologue), has been significantly associated with shorter DFI.⁶⁶

Footnotes

Key Points

Case notes

Cleo, a 13-year-old FN DSH cat, presented with a 5 x 3 cm mammary mass in her right caudal abdominal gland. She had a short history of being pyrexic and inappetent before presentation, and had clinical signs of concurrent hyperthyroidism (palpable goitre) and an elevated heart rate (250 bpm).

Funding

The author received no specific grant from any funding agency in the public, commercial or not-for-profit sectors for the preparation of this article.

Conflict of interest

The author does not have any potential conflicts of interest to declare.

References

Schneider

Dorn

Taylor

. Factors influencing canine mammary cancer development and postsurgical survival. J Natl Cancer Inst 1969; 43: 1249–1261.

Misdorp

. Tumors of the mammary gland. In: Meuten

(ed). Tumors in domestic animals. Oxford: Blackwell, 2002, pp 575–606.

Lana

Rutteman

Withrow

. Feline mammary tumors. In: Withrow

Vail

. (eds). Small animal clinical oncology 4th ed. St Louis: Elsevier, 2007, pp 628–636.

Hahn

Adams

. Feline mammary neoplasia: biological behaviour, diagnosis, and treatment alternatives. Feline Pract 1997; 25: 5–11.

Dorn

Taylor

Schneider

Hibbard

Klauber

. 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 1968; 40: 307–318.

Hayes

Jr Milne

Mandell

. Epidemiological features of feline mammary carcinoma. Vet Rec 1981; 108: 476–479.

Skorupski

Overley

Shofer

Goldschmidt

Miller

Sorenmo

. Clinical characteristics of mammary carcinoma in male cats. J Vet Intern Med 2005; 19: 52–55.

Hayes

Mooney

. Feline mammary tumors. Vet Clin North Am Small Anim Pract 1985; 15: 513–520.

Overley

Shofer

Goldschmidt

Sherer

Sorenmo

. Association between ovariohysterectomy and feline mammary carcinoma. J Vet Intern Med 2005; 19: 560–563.

10.

Misdorp

Romijn

Hart

. Feline mammary tumors: a case-control study of hormonal factors. Anticancer Res 1991; 11: 1793–1797.

11.

Moore

Ogilvie

. Mammary tumors. In: Ogilvie

Moore

(eds). Feline oncology. A comprehensive guide to compassionate care. Trenton, NJ: Veterinary Learning Systems, 2001, pp 355–367.

12.

de las Mulas

van Niel

Millan

Blankenstein

van Mil

Misdorp

. Immunohistochemical analysis of estrogen receptors in feline mammary gland benign and malignant lesions: comparison with biochemical assay. Domest Anim Endocrinol 2000; 18: 111–125.

13.

Martin de las Mulas

van Niel

Millan

Ordas

Blankenstein

van Mil

. Progesterone receptors in normal, dysplastic and tumourous feline mammary glands. Comparison with oestrogen receptors status. Res Vet Sci 2002; 72: 153–161.

14.

Millanta

Calandrella

Bari

Niccolini

Vannozzi

Poli

. Comparison of steroid receptor expression in normal, dysplastic, and neoplastic canine and feline mammary tissues. Res Vet Sci 2005; 79: 225–232.

15.

Millanta

Calandrella

Vannozzi

Poli

. Steroid hormone receptors in normal, dysplastic and neoplastic feline mammary tissues and their prognostic significance. Vet Rec 2006; 158: 821–824.

16.

Morris

Nixon

Bruck

Nasir

Morgan

Philbey

. Immunohistochemical expression of TopBP1 in feline mammary neoplasia in relation to histological grade, Ki67, ERalpha and p53. Vet J 2008; 175: 218–226.

17.

Cardazzo

Zappulli

Frassineti

Patarnello

Castagnaro

Bargelloni

. Full-length sequence and expression analysis of estrogen receptor alpha mRNA in feline mammary tumors. J Steroid Biochem Mol Biol 2005; 96: 109–118.

18.

Jacobs

Hoppe

Poehlmann

Ferracone

Sorenmo

. Mammary adenocarcinomas in three male cats exposed to medroxyprogesterone acetate (1990–2006). J Feline Med Surg 2010; 12: 169–174.

19.

Keskin

Yilmazbas

Yilmaz

Ozyigit

Gumen

. Pathological abnormalities after long-term administration of medroxyprogesterone acetate in a queen. J Feline Med Surg 2009; 11: 518–521.

20.

Zappulli

De Zan

Cardazzo

Bargelloni

Castagnaro

. Feline mammary tumours in comparative oncology. J Dairy Res 2005; 72: 98–106.

21.

Gimenez

Hecht

Craig

Legendre

. Early detection, aggressive therapy: optimizing the management of feline mam-mary masses. J Feline Med Surg 2010; 12: 214–224.

22.

Seixas

Palmeira

Pires

Lopes

. 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 2008; 84: 428–433.

23.

Seixas

Pires

Lopes

. Complex carcinomas of the mammary gland in cats: pathological and immunohistochemical features. Vet J 2008: 176: 210–215.

24.

Misdorp

Else

Hellmen

Lipscomb

. Histological classification of mammary tumors of the dog and the cat. Second Series. Washington DC: Armed Forces Institute of Pathology, 1999.

25.

Perez-Alenza

Jimenez

Nieto

Pena

. First description of feline inflammatory mammary carcinoma: clinicopatho-logical and immunohistochemical characteristics of three cases. Breast Cancer Res 2004; 6: R300–307.

26.

Owen

(ed). TNM classification of tumours in domestic animals. Geneva: World Health Organization, 1980, p 53.

27.

Weijer

Hart

. Prognostic factors in feline mammary carcinoma. J Natl Cancer Inst 1983; 70: 709–716.

28.

Papadopoulou

Patsikas

Charitanti

Kazakos

Papazoglou

Karayannopoulou

. The lymph drainage pattern of the mammary glands in the cat: a lymphographic and computerized tomography lymphographic study. Anat Histol Embryol 2009; 38: 292–299.

29.

Raharison

Sautet

. Lymph drainage of the mammary glands in female cats. J Morphol 2006; 267: 292–299.

30.

Raharison

Sautet

. The topography of the lymph vessels of mammary glands in female cats. Anat Histol Embryol 2007; 36: 442–452.

31.

Patsikas

Karayannopoulou

Kaldrymidoy

Papazoglou

Papadopoulou

Tzegas

. The lymph drainage of the neoplastic mammary glands in the bitch: a lymphographic study. Anat Histol Embryol 2006; 35: 228–234.

32.

Patsikas

Papadopoulou

Charitanti

Kazakos

Soultani

Tziris

. Computed tomography and radiographic indirect lymphography for visualization of mammary lymphatic vessels and the sentinel lymph node in normal cats. Vet Radiol Ultrasound 2010; 51: 299–304.

33.

MacEwen

Hayes

Harvey

Patnaik

Mooney

Passe

. Prognostic factors for feline mammary tumors. J Am Vet Med Assoc 1984; 185: 201–204.

34.

McNeill

Sorenmo

Shofer

Gibeon

Durham

Barber

. Evaluation of adjuvant doxorubicin-based chemotherapy for the treatment of feline mammary carcinoma. J Vet Intern Med 2009; 23: 123–129.

35.

Lana

Rutteman

Withrow

. Tumors of the mamma-ry gland. In: Withrow

Vail

(eds). Small animal clinical oncology. St Louis: Elsevier, 2007, pp 619–636.

36.

Muleya

Nakaichi

Taura

Yamaguchi

Nakama

. In-vitro anti-proliferative effects of some anti-tumour drugs on feline mammary tumour cell lines. Res Vet Sci 1999; 66: 169–174.

37.

Prop

Weijer

Spies

Souw

Peters

Erich

. Feline mammary carcinomas as a model for human breast cancer. I. Sensitivity of mammary tumor cells in culture to cytostatic drugs. A preliminary investigation of a predictive test. Anticancer Res 1986; 6: 989–994.

38.

Stolwijk

Minke

Rutteman

Hoekstra

Prop

Misdorp

. Feline mammary carcinomas as a model for human breast cancer. II. Comparison of in vivo and in vitro adriamycin sensitivity. Anticancer Res 1989; 9: 1045–1048.

39.

Jeglum

deGuzman

Young

. Chemotherapy of advanced mammary adenocarcinoma in 14 cats. J Am Vet Med Assoc 1985; 187: 157–160.

40.

Mauldin

Matus

Patnaik

Bond

Mooney

. Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats. J Vet Intern Med 1988: 2: 60–65.

41.

Novosad

Bergman

O’Brien

McKnight

Charney

Selting

. Retrospective evaluation of adjunctive doxorubicin for the treatment of feline mammary gland adeno-carcinoma: 67 cases. J Am Anim Hosp Assoc 2006; 42: 110–120.

42.

Borrego

Cartagena

Engel

. 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 2009; 7: 213–221.

43.

Rutten

Misdorp

Gauthier

Estrada

Mialot

Parodi

. Immunological aspects of mammary tumors in dogs and cats: a survey including own studies and pertinent literature. Vet Immunol Immunopathol 1990; 26: 211–225.

44.

Parodi

Misdorp

Mialot

Hart

Hurtrel

. Intratumoral BCG and Corynebacterium parvum therapy of canine mammary tumours before radical mastectomy. Cancer Immunol Immunother 1983; 15: 172–177.

45.

Fox

MacEwen

Kurzman

Dubielzig

Helfand

Vail

. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine for the treatment of feline mamma-ry adenocarcinoma – a multicenter randomized double-blind study. Cancer Biother 1995; 10: 125–130.

46.

MacEwen

Hayes

Mooney

Patnaik

Harvey

Passe

. Evaluation of effect of levamisole on feline mam-mary cancer. J Biol Response Mod 1984; 3: 541–546.

47.

London

. Tyrosine kinase inhibitors in veterinary medicine. Top Companion Anim Med 2009; 24: 106–112.

48.

Bellamy

Bader

Moussy

Hermine

. Pharmacokinetics of masitinib in cats. Vet Res Commun 2009; 33: 831–837.

49.

Daly

Sheppard

Cohen

Nabity

Moussy

Hermine

. Safety of masitinib mesylate in healthy cats. J Vet Intern Med 2011; 25: 297–302.

50.

Isotani

Tamura

Yagihara

Hikosaka

Ono

Washizu

. Identification of a c-kit exon 8 internal tandem duplication in a feline mast cell tumor case and its favorable response to the tyrosine kinase inhibitor imatinib mesylate. Vet Immunol Immunopathol 2006; 114: 168–172.

51.

Lachowicz

Post

Brodsky

. A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats. J Vet Intern Med 2005; 19: 860–864.

52.

Viste

Myers

Singh

Simko

. Feline mammary adenocarcinoma: tumor size as a prognostic indicator. Can Vet J 2002; 43: 33–37.

53.

Ito

Kadosawa

Mochizuki

Matsunaga

Nishimura

Sasaki

. Prognosis of malignant mammary tumor in 53 cats. J Vet Med Sci 1996; 58: 723–726.

54.

Hughes

Dobson

. Prognostic histopathological and molecular markers in feline mammary neoplasia. Vet J 2012; 194; 19–26.

55.

Castagnaro

Casalone

Bozzetta

De Maria

Biolatti

Caramelli

. Tumour grading and the one-year post-surgical prognosis in feline mammary carcinomas. J Comp Pathol 1998; 119: 263–275.

56.

Seixas

Palmeira

Pires

Bento

Lopes

. Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J 2011; 187: 65–71.

57.

Millanta

Lazzeri

Mazzei

Vannozzi

Poli

. MIB-1 labeling index in feline dysplastic and neoplastic mam-mary lesions and its relationship with postsurgical prognosis. Vet Pathol 2002; 39: 120–126.

58.

Preziosi

Sarli

Benazzi

Mandrioli

Marcato

. Multiparametric survival analysis of histological stage and proliferative activity in feline mammary carcinomas. Res Vet Sci 2002; 73: 53–60.

59.

Dias

Pereira P

Carvalheira

Gartner

. Cell proliferation in feline normal, hyperplastic and neoplastic mammary tissue – an immunohistochemical study. Vet J 2004; 168: 180–185.

60.

Castagnaro

Casalone

Nervi

Bozzetta

Caramelli

. Argyrophilic nucleolar organiser regions (AgNORs) count as indicator of post-surgical prognosis in feline mammary carcinomas. Res Vet Sci 1998; 64: 97–100.

61.

Preziosi

Sarli

Benazzi

Marcato

. Detection of proliferating cell nuclear antigen (PCNA) in canine and feline mammary tumours. J Comp Pathol 1995; 113: 301–313.

62.

Millanta

Calandrella

Citi

Della

Santa D

Poli

. Overexpression of HER-2 in feline invasive mammary carcinomas: an immunohistochemical survey and evaluation of its prognostic potential. Vet Pathol 2005; 42: 30–34.

63.

Rasotto

Caliari

Castagnaro

Zanetti

Zappulli

. An immunohistochemical study of HER-2 expression in feline mammary tumours. J Comp Pathol 2011; 144: 170–179.

64.

Millanta

Citi

Della

Santa D

Porciani

Poli

. COX-2 expression in canine and feline invasive mammary carcinomas: correlation with clinicopathological features and prognostic molecular markers. Breast Cancer Res Treat 2006; 98: 115–120.

65.

Millanta

Silvestri

Vaselli

Citi

Pisani

Lorenzi

. 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 2006; 81: 350–357.

66.

Maniscalco

Iussich

de las

Mulas JM

Millán

Biolatti

Sasaki

. Activation of AKT in feline mammary carcinoma: a new prognostic factor for feline mammary tumours. Vet J 2012; 191: 65–71.

Mammary Tumours in the Cat

Abstract

Practical relevance:

Clinical challenges:

Patient group:

Evidence base:

Epidemiology

Aetiology

Presentation

Diagnosis

Staging

Surgical treatment

Recommended approach

Chemotherapy

Other therapies

Prognosis

Clinical parameters

Histological parameters

Footnotes

Key Points

Case notes

Funding

Conflict of interest

References