Mammary gland tumours in the cat

Mammary tumours are the third most frequent tumour in the cat, after hematopoietic and skin cancers, and represent around 17% of feline malignant tumours in the female and 1-5% in the male cat._^6,7,49,14 Differently from what happens in the dog, around  85% of mammary lesions are malignant,_¹⁸hence in terms of treatment  an early diagnosis and the exact understanding of the lymphatic and haematic drainage of the mammary glands are fundamental.

Inflammatory carcinoma, a highly malignant although quite rare tumour, has recently been described also in the cat,_⁴² just as in humans and in the dog.

In view of their specific molecular characteristics and of the behaviour of malignant histotypes (modality of metastasisation), mammary tumours of the cat are considered a good model for the study of the more aggressive, non hormone-dependent forms present in human mammary cancers._³¹

AETHIOLOGY AND PATHOGENESIS

In the feline species, just like in the dog, hormones seem to play an important role in the pathogenesis of mammary tumours. In a recent study, Overley et al. (2005) have in fact shown the protective effect, also in cats, of sterilisation before the 1_^st year of life, in preventing malignant mammary tumours (86% risk reduction); the risk is reduced by 91% if sterilisation is done before the cat is 6-months old, while pregnancies, the age at first delivery and the number of kittens are not considered risk factors. In addition, early sterilisation (within 24 weeks of age) did not have a negative impact on behaviour, and did not entail greater risks for other systemic diseases._¹²

The use of synthetic progestogens or of the association oestro-progestogens has furthermore been correlated to a 3-fold increase in the risk of developing benign and malignant mammary tumours both in females and in males, as well as in wild felidae._{^{29,23,31,17,50,14}} This may be explained by the fact the healthy tissues, and the tissue of benign proliferative lesions, express a low level of oestrogen receptors (ER) and a moderate level of progesterone receptors (PR), while the expression is almost totally absent in the more malignant forms._^34,28,2

Furthermore, just like in women and in the dog, also in the queen alterations in oncogenes may correlate to a more malignant expression of mammary tumours. Among such oncogenes,  we may include Her-2/neu (c-erbB-2), the hyperexpression of which is found in 10-40% of human mammary carcinomas, in whom it correlates with a poorer prognosis;_⁵¹ in the cat such percentage is even greater,_^27,6,35 confirming the existing correlation between oncogenes  and malignancy also in this species.

Sayasith et al. (2009) have also shown that the COX-2 enzyme is expressed in 87% of the cases they examined, although only in 5% the levels were extremely elevated. This is also in agreement with what has been observed in women and in the dog, meaning that non steroidal anti-inflammatory drugs which selectively inhibit such enzyme may be of potential benefit in the therapy of malignant mammary tumours in the cat.

Finally, the Mouse Mammary Tumour Virus (MMTV) has been isolated also in the normal and neoplastic mammary tissue of cats, however its role in the development of mammary tumours has not yet been totally understood._¹³

BIOLOGY

Although any breed may be affected, a greater incidence has been reported in common cats and especially in the Siamese, in which the risk of developing mammary tumours seems to be two times greater compared to other breeds,_¹⁸ and may be affected at a younger age. The median age at diagnosis is 10-12-years old, slightly higher in males, however the disease may affect both extremely young or extremely old subjects, although the probability increases when cats are over 6-years old._¹⁸

Data on the predilection of the tumour for a specific mammary gland over the others are contrasting,_⁷ hence any mammary gland may be considered at risk of malignant forms, which usually have multiple involvement, with at least 50% of subjects affected on more mammary glands at the same time. Mammary tumours are extremely fast growing, consequently early ulcerations are frequent (present in around 25% of cases) and are a sign of malignancy, as are tumour adhesions to the underlying skin or muscular fascia. The invasion of lymphatic vessels and of lymph nodes is also frequent, even if the volume increase of regional lymph nodes is a late event._⁷Metastases develop in around 80% of cats with malignant mammary tumours and prevalently infiltrate the regional lymph nodes, lungs, pleura, liver and, more rarely, adrenal glands, kidneys, diaphragm and bone _^9,10,11,33 (Fig. 1). Nipples may appear edematous, and at times a brownish secretion may be produced.

If not treated, the mean life expectancy of a cat with malignant mammary tumour is of around 1 year.

Just like in the dog, most feline mammary tumours originate from the epithelial component of the gland, giving rise to adenomas and adenocarcinomas; only a minority originates from the connectival tissue, but in these cases the malignancy of the tumour is often high. There are also mixed forms, defined as carcinosarcoma or malignant mixed tumour, characterized by the presence of malignant cells originating from both cell lines and by a poor prognosis. The presence of a myoepithelial component has instead been correlated to a better prognosis._⁴

Differently than in the dog, instead, the hystotype which is more frequently encountered is adenocarcinoma, which represents 80% of malignant forms and is in turn subdivided into various subtypes, described with minor variations by pathologists, but all characterised by a similar clinical aggressiveness (Table 1)._¹⁸ As in the dog, inflammatory carcinoma is a totally different issue, but it is even rarer in the cat.

Benign formsinstead, which are much rarer in the cat, are divided into neoplastic forms (adenoma, papilloma, benign mixed tumour) and non-neoplastic forms (ductal, lobular and fibroepithelial hyperplasia) (Table 1). Table 1 illustrates the classification proesented by Misdorp (1999) and then adjusted by Lana (2007). In general, the clinical presentation of benign tumours is similar to that of malignant types; the median age at onset is slightly lower, however they are characterised by  a slower growth,  so the final diagnosis is often made with the histologic examination of the excised mass.

Among the non-neoplastic, benign forms, a special interest has been gained by fibroepithelial hyperplasia  (or fibroadenomatous hyperplasia, FH), due to its considerable impact on the life of affected patients. Fibroepithelial hyperplasia affects especially queens when they reach sexual maturity or during pregnancy, because of the influence of progesterone, however it can also be found in sterilised queens or in males treated with high doses of medroxyprogesterone or megestrol acetate._¹⁹ The result is an exaggerated response of the mammary gland to the progestinic stimulus, with a consequent considerable and rapid volume growth of the organ.

Table 1. Histologic classification of feline mammary tumours (Lana 2007 - Misdorp 1999)

DIAGNOSIS

Diagnosis, just like in the dog, is often made late, especially in long-haired cats and in the case (frequent in queens) of “slate-like” neoformations, meaning the presence of  a diffuse nodular area within the mammary parenchyma,  difficult to identify without a careful palpation of the organ. Signs and symptoms may be strikingly evident only in the case of fibroepithelial hyperplasia, which is characterised by a rapid evolution and is dominated by an exaggerated and sudden volume increase of the mammary glands, which may even interfere with the normal gait of the animal (Figs. 2a, b and c) and may rapidly become ulcerated.

Signalment is, as usual, extremely important. Special attention must be paid to the hormonal status of the animal (e.g. sterilised or intact, administration of oestro-progestogens, possible mating/pregnancy under way, age).

The clinical examination must include palpation of both mammary rows and of the explorable lymph nodes (axillar, inguinal); specifically, a careful assessment of the number, size and eventual adhesion of the mammary masses with the deep muscular layers is necessary (Figs. 3a and b), in order to stage the tumour (the “T” of the TNM staging system of the WHO_³⁸) (Tab. 2). Before continuing with the examination, it is first necessary to assess the overall health status of the animal with a full haematochemical examination,  which must include FIV and FeLV tests and eventually also a coagulation profile – in the case of suspected inflammatory carcinoma, which may potentially be associated to disseminated invravascular coagulation - , and finally urinalysis. In case of suspected fibroepithelial hyperplasia, in a non-pregnant animal, progesterone blood values should be tested, or, if the queen is sterilised, the possible presence of ovarian residues should be ascertained._⁷

Diagnosis and tumour staging are completed with radiography of the chest,  with two latero-lateral views as a minimum, in order to identify eventual metastases, and with ultrasonography of the abdomen, in order to assess the medial, iliac lymph nodes, and to verify any presence of foetuses, in the case of fibroepithelial hyperplasia. Recently, the routine use of computed tomography of the chest has allowed the identification of lung metastases early on, which were otherwise invisible, proving useful also for the assessment of sternal lymph nodes, which are difficult to analyse with radiography._³⁶

Citology of the primary mass is rarely done, as most mammary neoformations in the cat are malignant, while it can be indicated for the assessment of tributary lymph nodes, in order to decide on their eventual removal wih the excision of the mammary gland row and to give  timely prognostic indications to the owners.

The final diagnosis, however, can only be based on the histology of the lesion (Figs. 4a, b and c), done during the therapeutic surgery, which also allows the evaluation of the complete removal of the mass (the entire resected specimen must always be sent for histology!).

Table 2. Modified staging system of mammary tumours in the cat (Owen LN, 1980)

THERAPY

Similiarly to the dog, also in the cat the treatment of choice for malignant mammary tumours consists in the surgical removal of the tumour, with the exception of inflammatory carcinoma. Differently than in the dog, however, in cats it is always necessary to remove the entire mammary gland row of at least one side (Figs. 5a, b and c), and possibly to do a bilateral mastectomy. In view of the extent of such surgery, however, when possible it is advisable to do the surgery in two steps, with an interval of one month between the two procedures.

More conservative procedures, such as regional mastectomy or mammectomy, are reserved to those cases in which the benign nature of the lesion has been previously confirmed by histology. The  inguinal lymph node is always to be excised together with the mammary glands;  the axillary lymph node is excised only if palpable, by means of an additional incision, even if an increase in volume of this lymph node is a negative prognostic factor and the prophylactic excision of the lymph node is being debated._¹⁸

The need for such aggressive interventions is explained by the anatomy of mammary glands, as well as by the biology of the tumour, and specifically of its blood supply (Fig. 6). Blood arrives from the cranial and caudal epigastric artery on each side, which then branches out with some anastomotic vessels on the two sides, at the level of the umbilicus; the veins, satellite veins of the arteries, have an interconnection between the two rows, which passes above the arteries._^48,7 The spread of tumour cells may also take place from the two thoracic glands, via the internal thoracic veins and/or the intercostal vessels._^25,7

The lymphatic drainage is instead less easily determined, especially in the presence of a tumour, as the drainage may be altered compared to the normal anatomy. Based on a review of literature._{^{44,45,7,39,40}}  it may however be stated that the primary site of drainage is represented by axillary and inguinal lymph nodes;  the first drain the lymph from the two thoracic glands (T1 and T2), and occasionally from the first abdominal gland (A1), while the inguinal lymph nodes drain A2 and occasionally A1. Differently than what happens with blood supply, a connection between the lymphatic vessels on both sides has currently not been identified, neither between the single mammary glands; finally, the metastatic spread to medial sternal and iliac lymph nodes occurs only sporadically, and  these are usually a second lymph nodal station, consequently if the primary station is clean their involvement is rare.

The excision of the tumour should often also include one underlying fascial plane and, in case of adhesions to deep layers, the abdominal musculature, this in consideration of the greater aggressiveness of this tumour in this animal species. In cases in which a full thickness segment of the abdominal wall has to be removed, the reconstruction may be done exploiting the elasticity of the residual musculature, or using a synthetic mesh covered with omentum.

All the resected biological material  must be sent to the laboratory for a full histologic examination in order to assess the excision margins.

As for the need of performing a concomitant ovariohysterectomy, there is no uniformity of opinion, however the most frequent orientation is to consider it irrelevant, especially in older subjects._¹⁸

The healing of the wound usually takes place without complications, especially in the case of unilateral mastectomy. In the case of bilateral mastectomy or of obese animals a partial dehiscence of the wound is possible, which however usually heals by second intention, as is the formation of seromas.

The usefulness of chemotherapy in the treatment of feline mammary tumours is still debated. In a study by Jeglum et al. (1985), done in queens with inoperable tumours, the combination of doxorubicin and ciclophosphamide showed a response in 45% of cases with an increased survival. This positive result was apparently confirmed by Novosad et al. (2006), who reported an increase in disease free survival in subjects which had completed 5 treatment cycles with doxorubicin (1 mg/kg IV every 3 weeks) compared to subjects which underwent an inferior number of cycles, although in the study the only factor which had an impact on survival was the initial size of the tumour. McNiell et al. (2009) have instead shown, in a comparative trial, the great variability which exists in terms of response to therapy between subjects treated with surgery alone or whith surgery combined with chemotherapy; based on the results the group expressed doubts with regards to the real efficacy of chemotherapy, if not in selected cases. In the same year Borrego et al. (2009) reported, in a retrospective study on 23 cats, that not even che combination of aggressive surgery, doxorubicin and meloxicam was beneficial versus the therapy without the COX-2 inhibitor.

Other drugs which are at times used are vincristine and mitoxantrone, however case reports are sporadic and the results not encouraging. 5-fluorouracil, used in women and in the dog, cannot instead be used in the cat as it has been associated with lethal nerotoxicity.

The opinion of the Author is that the use of doxorubicin, associated or not with a COX inhibitor, is advisable only in the case of particularly aggressive neoplasms or when the presence of vascular or lymphatic emboli or lymph nodal metastases have been reported.

Radiotherapy is not currently considered as a therapeutic option for feline mammary tumours, also because one of the biggest problems in controlling such tumours is represented by the metastatic spread.

Hormonal therapy, as well as other forms of treatment, such as the use of immunostimulants,_²⁰are not currently advisable in the cat. A recent study_⁴¹ has however shown the synergic action between recombinant feline interpheron- ω and antracyclines in cell cultures of feline and canine mammary tumours.

In the case of fibroepithelial hyperplasias, the disease may regress spontaneously after delivery. If the origin of the problem was the administration of megestrol acetate or medroxyprogesterone, such drugs must be immediately suspended. In the presence of mammary ulcerations or oedemas, a good analgesic and antibiotic therapy are indicated. Otherwise, ovariectomy, which eliminates the hormonal stimulus, leads to the involution of the hypertrophic mammary tissue within a variable time span ranging between 3-4 weeks and 5-6 months. At times, however, the surgery is difficult because of the considerable size of the mammary glands; in such cases a lateral flank approach is indicated. The concomitant mastectomy may not be well tolerated, owing to the huge amount of tissue which is to be removed. To overcome such inconveniences, an antiprogestogen therapy with aglepristone is currently advised,_⁷ having first excluded an eventual pregnancy, as the drug may induce abortion. Treatment protocols with aglepristone vary depending on the Authors and on the origin of the progesterone (endogenous or long acting drugs); Weherend et al., (2001) suggest the dose of 10 mg/kg subcutaneously for 4-5 consecutive days; Gorlinger et al. (2001) report that if the origin of the problem is iatrogenic, a dose of 20 mg/kg once a week, until remission, is appropriate: Finally, Jurka and Max (2011) propose 10 mg/kg for 2 consecutive days, to be repeated once a week, until remission, which usually takes place within 3-4 weeks.

PROGNOSIS

While for benign forms and for fibroepithelial hyperplasia the prognosis, following surgical excision or pharmacological treatment of FH, is good, in the case of adenocarcinoma the high risk of metastatic spread (to the lungs or to regional lymph nodes) makes in most cases the prognosis guarded.

The important risk factors in the treatment of feline mammary tumours are:

• size of the tumour: masses greater than 3 cm in diameter have a poorer prognosis, in both females and males._⁴⁹ The median survival in cats stages T1 and T2 is in fact of 54 and 24 months, respectively_²⁰, while for stage T3 it goes down to 4-12 months;_⁵²
• histologic grade: Seixas et al. (2011), in a trial on 92 carcinomas, reported that in most cases (47,8%) the tumours are highly invasive (G3) and that there is a significan correlation between histologic grade, age of the animal, size of the tumour and skin ulcerations. In addition, the histologic grade was significantly correlated to median survival, equal to 6 months for queens with G3 tumours and 36 months for queens with G1 tumours. The longest survival was associated to complex and tubulopapillary carcinomas, the shortest to solid and micropapillary carcinomas. In the same study an inferior survival was reported in cases in which there was, at presentation, the presence of neoplastic emboli and lymph nodal involvement;
• expression of ki-67: a positive correlation has been reported between the increased expression of this cell proliferation index and a decrease in survival;_^3,47
• extent of surgery: although some studies_⁵² report that the extent of surgery does not have an impact on survival, some Authors_^21,33 have shown a greater survival in queens undergoing a bilateral mastectomy compared to those which have undergone a unilateral intervention (917 and 348 days, respectively). Given the aggressive nature of this tumour, and while attending new confirmations, the opinion of the Author is that in most cases of mammary tumours in the cat, radical surgery should be preferred;
• clinical stage: clearly the presence of metastases at presentation is a negative prognostic factor, but also the site of metastases may have a predictive value; according to the study by Novosad et al. (2005), in fact, queens with lung metastases have a post-treatment survival of 331 days, compared to 1500 days for queens with the involvement of only regional lymph nodes;
• molecular markers: just like in women and in the dog, also in the cat the correlation between some molecular factors and the malignancy of mammary tumours is emerging. Among these we have A_³², p53_³², RON_⁵, VEGF_²⁶, HER-2_²⁷, STAT3_⁴³, TopBP1_³⁰, AKT_²².

For a more detailed explanation refer to specific studies.

PREVENTION

-  does sterilisation prevent the development of malignant mammary tumours?

although less clearly than in the dog, it is known that feline mammary tumours are under the influence of hormones. Early sterilisation is consequently suggested in order to reduce the risk of developing malignant tumours and to prevent fibroadenomatous hyperplasia;

-  and pregnancy?

Pregnancy,_²⁹ the number of pregnancies, the number of kittens delivered and the age at first pregnancy do not seem to influence the development of malignant mammary tumours. In some cases pregnancy, especially in young subjects, may induce the appearance of fibroadenomatous hyperplasia;

- and the use of oestrogens and progestogens?

the use of synthetic progestogens may cause the appearance of fibroadenomatous hyperplasia in females, while the association of oestrogens and high-dose progestogens, or of progestogens administered on a continued basis may cause the formation of malignant neoplasms;_²⁹

-  is sterilisation at the time of excision of the mammary tumour useful?

while sterilisation is surely useful for the prevention of fibroadenomatous hyperplasia, its protective role against malignant tumours, if done at an advanced age, has not been proven.

Inflammatory carcinoma (IC)

The first report on the presence of this disease in the cat is by Pérez-Alenza et al. (2004). The 3 queens described were all non-ovariectomized and had undergone a mastectomy from 1 to 4 months before, for the presence of a malignant cancer. The inflammatory carcinoma, based on the clinical history and the clinical signs, was therefore considered as a secondary tumour. In all cases a rapid development of the clinical signs was observed, with the presence of oedema and erythema, extreme local pain, areas of skin ulcerations, suture rejection of the previous surgery and involvement of the corresponding limbs. Citology of the lesion, done in two cases, showed severe inflammation with numerous neutrophilic granulocytes (differently than in the dog) and the presence of some cells with signs of malignancy. Histology classified the lesions as follows:  two cases of papillary carcinoma and one case of tubular carcinoma, all grade III. The presence of neoplastic emboli in the lymphatic vessels of the dermis is a characteristic of inflammatory carcinoma in both the dog and the cat, while in this latter species a severe dermal inflammation of the adipous tissue has been observed, something not described in other species.

The survival of the 3 queens was of 10-45 days from the time of diagnosis; all subjects were euthanised due to the rapid deterioration of overall conditions. No surgical or medical treatment is currently advised for this type of tumour.

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