DISEASE of the MAMMAE of DOGS

From a disease perspective, the 2 main disease categories are inflammation and neoplasia. Clinically, there are others, and as pathology is a bridge between the disease and clinical presentation, it behoves a pathologist to be knowledgable about the others too.

Contents

Anatomy and terminology

Functional disorders

  1. Galactostasis
  2. Agalactia
  3. Galactorrhea
  4. Mammary hypertrophy

Mastitis

Neoplasia

Mammary disease in male dogs

 

Anatomy and terminology

The official terminology of mammary tissue is a little different to what is being taught in most veterinary schools. The official name for a quarter (in cattle) or 'mammary gland' in most species is mamma. Embryologically, the ventrolateral ectoderm of the embryo becomes the mammary ridge and then the mammary complex. Mammary buds push into mesenchyme with their number equaling the number of mammae: Dogs have 10 mammae. Sprouts form from each mammary bud, and the number equals the number of papillary ducts (and therefore mammary glands) per mamma: bitches have 8 to 14 mammary glands per mamma and thus there are 8-14 papillary ducts per papilla. Mammae develop in male embryos, but in domesticated species, they only regress fully in the stallion.


As puberty approaches, there is branching of ducts mediated by prolactin, growth hormone, insulin-like growth factors, and many other factors. There is an intimate interaction between the mesenchyme and epithelium in the formation of ducts and alveoli. Mammary development is maximal at the onset of lactation. Milk flows from alveoli through the lactiferous ducts to the papillary duct.
When suckling stops, mammary secretion stops and the glands involute. Involution involves a reduction in the area of secretary epithelium and increase the relative amount of stroma of the gland. When secretion ceases completely, mammary fluid is resorbed.

 

 

Santos M, Marcos R, Faustino AM. Histological study of canine mammary gland during the oestrous cycle. Reprod Domest Anim. 2010; 45: e146-54. doi: 10.1111/j.1439-0531.2009.01536.x. PMID: 19895392.

Functional disorders

Galactostasis

Galactostasis is milk retention, and there is no systemic illness, even though the glands become engorged, hot, and painful. It occurs after parturition, weaning or in pseudopregnancy and is thought to result from inadequate oxytocin release because of fear, stress, or lack of mammary stimulation.

A reveiw of this, referring to 'congestion' is provided by Vasiu et al (2021).

Vasiu I, Dąbrowski R, Tvarijonaviciute A. Lactation-related mammary gland pathologies-A neglected emergency in the bitch. Reprod Domest Anim. 2021; 56: 208-230.

Agalactia

This is a rare condition, and the cause is unknown. There is failure of mammary development and therefore lactation.

Galactorrhoea (inappropriate lactation, precocious lactation). 

Inappropriate lactation occurs in several scenarios. It occurs at the termination of diestrus where prolactin surge in response to a reduction in  progesterone concentration causes milk production. It occasionally occurs following ovariohysterectomy during diestrus. It also occurs in juvenile or speyed dogs when exposed to human medication of estrogen replacement therapy. Mammary development is one of a number of changes (vulva swelling and estrus).

Mammary hypertrophy

Mastitis

Mastitis is inflammation of the mammary gland, usually in response to infection.

Inflammation of the papilla is papillitis.You will also see mammillitis (inflammation of the nipple) and thelitis (inflammation of the teat)

Vasiu et al (2021) reviewed mastitis in dogs.

Vasiu I, Dąbrowski R, Tvarijonaviciute A. Lactation-related mammary gland pathologies-A neglected emergency in the bitch. Reprod Domest Anim. 2021; 56: 208-230.

 

Bacterial mastitis

Mammary infections in dogs occur early in lactation or pseudopregnancy.  Staphylococci, streptococci and  E. coli are the major isolates. They cause abscesses and/or neutrophilic inflammation resulting.  The glands become swollen, large, firm, and edematous.  It may be superimposed on mammary hyperplasia or mammary neoplasia, especially tumors of ducts.  Systemic illness is usually seen.  There are no studies of the effect of mastitic milk on puppies, however logic would suggest that exposure of puppies to pathogens is not a good idea.

Inflammatory carcinoma is an unfortunate diagnosis. It was first made in women, and is a clinical diagnosis. This syndrome is where there is rapidly growing neoplasm of the breast causing erythema, edema, firmness, heat and pain.  It develops especially with adenocarcinoma; the tumour may be diffuse involving multiple glands.  Prognosis is poor.  This condition can be differentiated from mastitis in that it is not associated with lactation.  Lymphatics become occluded with neoplastic emboli which causes swelling and erythema or even limb swelling.  The initial clinical diagnosis is often mastitis and not neoplasia.

Mycotic mastitis

Ditmer and Craig (2011) reported on 3 cases of pyogranulomatous to granulomatous mastitis with Blastomyces dermatitidis. Two of the dogs also had lymph node and pulmonary involvement.

 

Ditmyer H, Craig L. Mycotic mastitis in three dogs due to Blastomyces dermatitidis. J Am Anim Hosp Assoc. 2011; 47: 356-358.

Mammary Hyperplasia, Dysplasia and Atypia

Papilla

Melanosis of skin of papilla

Ductal hyperplasia/adenomatous hyperplasia

    Schulman et al (2022) reported on 10 cases of teat "sinus" and duct adenomatous hyperplasia. 5 of the dogs had multiple examples. 16 of 17 examples were pigmented. They involved the epidermis of the papilla and extended from there to the papillary duct. There was often squamous differentiation and ducts. Many melanocytes and melanomacrophages were present.

     

    Schulman FY, Goldschmidt MH, Hardcastle M, Zappulli VEG. Teat sinus and duct adenomatous hyperplasia in dogs. Vet Pathol. 2022; 59: 256-263.

       

Mamma

Duct ectasia

Lobular hyperplasia

Epitheliosis

This change occurs in the intralobular and interlobular lactiferous ducts where there the cells are hyperchromatic and are larger and have slight anisokaryosis, with papillary projections into the lumen. It is often multifocal.

Epitheliosis within a mamma with a mammary neoplasm had a statistically significant association to

  1. malignant tumors (P = .044),
  2. worse clinical stages (P = .013),
  3. lymph node metastasis (LNM, P = .021),
  4. higher histological grade tumors (P = .035),
  5. horter overall survival (OS)

Valdivia G, Alonso-Diez Á, Alonso-Miguel D, Suárez M, García P, Ortiz-Díez G, Pérez-Alenza MD, Peña L. Epitheliosis is a histopathological finding associated with malignancy and poor prognosis in dogs with mammary tumors. Vet Pathol. 2022; 59: 747-758.

Papillomatosis

Fibroadenomatous change

Gynecomastia

Mammary Neoplasia

General introduction

Mammary tumors are very common in female dogs, especially those who were not spayed at an early age.

About one half of mammary tumors are histologically categorised as malignant. This is very misleading and should not be used. Histological features of malignancy should only be used in classification and not to predict outcome. They are not the same. Depending on the study, mammary carcinomas metastasise and or cause death in about 10% (Cotchin), 27% (Howell et al ), 50% (Else), 58% (Schneider), 72% (Bostock 1975).

Many publish studies ascribing some factor with malignancy as defined by histological features of malignancy (ie are classified as carcinomas). What they are doing is relating a factor with a histological indicator of malignancy and not with the clinical outcome. As a practical guide, the following are publications that one can use in a diagnostic setting to provide guidance to veterinarians and their clients.

Occurrence of Neoplasia  The occurrence is recorded at 2,400 per 100,000 bitches (2-4%).

Predisposing factors

The window of susceptibility is up to 2 years of age.  Ovariectomy especially and a high protein diet decreases susceptibility.  Medroxyprogesterone acetate (MA) treatment and  being a purebred increases it.

Ovariectomy effect
Prevalence
prior to 1st estrus  - 0.05%
after 1st estrus      - 8%
after 2nd estrus     - 26%
late ovariectomy has some protective effect

In a meta analysis,Stavisky and White (2022) found that the evidence that the reduced risk of developing a neoplasm and early spaying was considered weak but consistent.

Banchi examined the disease free survival in dogs with mastectomy and ovariectomy. They examined 225 cases and 116 cases underwent surgery and 46 had mastectomy alone and 18 were already spayed. 52 were spayed at removal of the neoplasm. They looked at benign and malignant based on classification and grading, and tumor size. Dogs with smaller tumors survived longer than those with larger tumors. Those what were spayed had a statistically different Disease Free Survival.

 

Banchi P, Morello EM, Bertero A, Ricci A, Rota A. A retrospective study and survival analysis on bitches with mammary tumours spayed at the same time of mastectomy. Vet Comp Oncol. 2022; 20: 172-178.

Stavisky J, White C. Does spaying at a younger age reduce dogs' risk of developing mammary tumours? Vet Rec. 2022; 190: 123-125.

Classification

There are many 'classification' papers outlining surveys of mammary tumors and numbers. Most regard the histological classification of carcinoma as indicating malignancy.

Goldschmidt et al (2011) provides a comprehensive outline of mammary classification, and this has been accepted by the Veterinary Cancer Society/American College of Veterinary Pathology, Oncology Pathology Working Group as the classification to use.

The scheme is adapted from Goldschmidt et al 2011 and Zappulli et al 2019. Rather than using the classical Squamous/adenosquamous/adenocarcinoma paradyme, this is simplified.

A. NEOPLASIA OF THE PAPILLA

    1. ductal adenoma
    2. intraductal papillary adenoma
    3. ductal carcinoma
    4. intraductal papillary carcinoma
    5. carcinoma with epithelial infiltration (Pagets)

B. NEOPLASIA OF THE GLANDS

  1. Epithelial and Mixed Neoplasms of the glands
    1. "Benign"
      1. Glandular
        1. Simple adenoma
          1. tubular
          2. papillary
          3. tubulopapillary
      2. Complex and mixed
        1. Complex adenoma
        2. Fibroadenoma
        3. Myoepithelioma
        4. Benign mixed mammary tumor
      3. Ductal
        1. Intraductal papillary adenoma
        2. Ductal adenoma (basaloid)
        3. Ductal adenoma with squamous change
    2. "Malignant"
      1. Glandular
        1. Carcinoma in situ
        2. Simple Carcinoma
          1. tubular
          2. tubulopapillary
          3. cribriform
          4. solid
          5. invasive micropapillary
          6. comedocarcinoma
          7. anaplastic
        3. Complex and mixed
          1. Carcinoma arising in a complex adenoma
          2. Complex carcinoma - complex type
          3. Carcinoma and malignant myoepithelioma
          4. Mixed carcinoma - with cartilage and bone
      2. Ductal
        1. Ductal carcinoma
        2. Intraductal papillary carcinoma (including papillary cystic carcinoma)
      3. Special types
        1. Squamous cell carcinoma
        2. Adenosquamous carcinoma
        3. Mucinous carcinoma
        4. Lipid rich carcinoma
        5. Spindle cell carcinoma
        6. Inflammatory carcinoma
  2. Carcinosarcoma - malignant mixed mammary tumor
  3. Mesenchymal neoplasms - sarcomas
    1. Osteosarcoma
    2. Chondrosarcoma
    3. Fibrosarcoma
    4. Hemangiosarcoma
    5. others

 

These and other types are indicated below in Prognosis

Some classification schemes and usage are different, such as Nakagaki et al (2022)

 

Nakagaki KYR, Nunes MM, Garcia APV, Nune FC, Schmitt F, Cassali GD. Solid carcinoma of the canine mammary gland: a histological type or tumour cell arrangement. J Comp Path 2022; 190: 1-12.

Prognosis

Size

Dogs with mammary tumours that are greater than 3 cm in diameter have a lower overall length of survival and if the size of the tumour is more than 5 cm in diameter the likelihood of malignancy is increased further.

#
dead
6mths
12 mths
24 mths
Pena et al (2013)
>3cm
85
70
60
Santos et al (2011)
>2.9
85
80
60

Gedon et al (2021) found an increasing correlation between a diagnosis of carcinoma and size.

 

Gedon J, Wehrend A, Failing K, Kessler M. Canine mammary tumours: Size matters-a progression from low to highly malignant subtypes. Vet Comp Oncol. 2021; 19: 707-713.

Peña L, De Andrés PJ, Clemente M, Cuesta P, Pérez-Alenza MD. Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up: relationship with clinical and histological characteristics. Vet Pathol. 2013; 50: 94-105.

Santos M, Carla Correia-Gomes C, Santos A, de Matos A, Rochaa E, Lopes C, Dias Pereira P. Nuclear pleomorphism: Role in grading and prognosis of canine mammary carcinomas. The Vet J 2014; 200: 426-433

Distant metastases

Rasotto R, Zappulli V, Castagnaro M, Goldschmidt MH. A retrospective study of those histopathologic parameters predictive of invasion of the lymphatic system by canine mammary carcinomas. Vet Pathol 2012; 49: 330-340.

Metastasis to lymph nodes

The following table summarises the prognosis of finding metastasis to lymph nodes. numbers are % survival at the time points.

# dogs
6mths
12 mths
24 mths
Median
Hellman et al (1993)
202
40
25
15
 
Pena et al (2013)
65
18
 
Szczubial and Lopuszynski (2011) >2mm
14
7
15 mths
Szczubial and Lopuszynski (2011) <2mm
37
50
8mths
de Araújo et al (2015)
97
70
40
25
 
           

What constitutes metastasis to lymph node? Publications mostly just use 'metastasis', assuming we all know what that means. In the human world, there is a size of clusters of epithelial cells in a lymph node that represents a true metastasis - it 0.2mm.

Hellman et al (1993) 202 cases, Six month survival with metastasis to lymph node was 40%, 12 month survival was 25% and two year survival 15%.

Szczubial and Lopuszynski (2011) found that if there were no epithelial cells in the lymph node, 15 of 29 dogs were alive after 2 years, median 19 mths. If there were epithelial cells but less than 2mm diameter, 4 of 8 were alive at 2 years, median 16 months. If greater than 2mm, 1 of 14 was alive at 2 years, median was 8 months

de Araújo st al (2015) found that the survival of dogs without metastasis to the lymph node was ~70% over 2 years, and that those metastases that were >7mm had a worse prognosis.

Coleto et al (2018) examined lymph nodes from dogs and used immunohistochemistry to identify micrometastasis and occult isolated tumor cells. They found no difference in prognosis between dogs WITH occult isolated tumor cells and those with no occult isolated tumor cells. Micrometastasis was more common in the cortex and isolated cells in the medulla.

Coleto AF, Wilson TM, Soares NP, Gundim LF, Castro IP, Guimaraes EC, Bandarra MB, Medeiros-Ronchi AA. Prognostic Value of Occult Isolated Tumour Cells within Regional Lymph Nodes of Dogs with Malignant Mammary Tumours. J Comp Pathol 2018; 158; 32-38

Intravascular invasion - tumour emboli

Percentage survival

#
6mths (%) 12 mths (%)
2yrs(%)
Santos et al 2014
49
70
60
50
Stevens
   
Diessler et al (2017)
36
68
52
   
Rasotto et al (2017)
52
19
0
   
Seung et al (2021)
16
25
10
0

Im et al (2014) classified 648 histologically and 159 on molecular and hormonal characteristics. In their study, 40 of 340 (11.4%) had lymphatic invasion.

Diessler ME, Castellano MC, Portiansky EL, Burns S, Idiart JR. Canine mammary carcinomas: influence of histological grade, vascular invasion,
proliferation, microvessel density and VEGFR2 expression on lymph node status and survival time. Vet Comp Oncol 2017: 17: 450

Im KS, Kim NH, Lim HY, Kim HW, Shin JI, Sur JH. Analysis of a new histological and molecular-based classification of canine mammary neoplasia.Vet Pathol. 2014; 51: 549-559.

Rasotto R, Berlato D, Goldschmidt MH, Zappulli V. Prognostic Significance of Canine Mammary Tumor Histologic Subtypes: An Observational Cohort Study of 229 Cases. Vet Pathol. 2017 Jul;54(4):571-578.

Santos M, Carla Correia-Gomes C, Santos A, de Matos A, Rochaa E, Lopes C, Dias Pereira P. Nuclear pleomorphism: Role in grading and prognosis of canine mammary carcinomas. The Vet J 2014; 200: 426-433

Seung BJ, Cho SH, Kim SH, Bae MK, Lim HY, Kwak SW, Sur JH. Impact of Histological Subtype on Survival in Canine Mammary Carcinomas: a Retrospective Analysis of 155 Cases. J Comp Pathol. 2021; 186: 23-30.

Stevens et al 2016

 

Peripheral invasion

From the earliest investigations of the prognosis of mammary carcinomas, peripheral invasion was recognised as an important feature. Peripheral invasion is a low power observation. Early on, those carcinomas with no peripheral invasion were regarded as being in situ adenocarcinomas. Comparing early studies with later ones may not be reasonable.

Bostock (1975) found that invasion was an important feature in tubular and solid adenocarcinomas but not papillary adenocarcinomas

Rasotto et al (2012) used lymphatic invasion and lymph node metastasis as the indicators of a poor prognosis and found that peripheral invasion, and a micropapillary pattern were predictive.

Prognosis of invasive carcinomas (survival)
#
type 6 mths
12 mths
2 yrs
Bostock (1975)
62
non invasive tubular
86%
26
Invasive tubular
50%
29
Non invasive solid
73%
35
invasive solid
26%
Stevens
60
50

40

Rasotto R, Zappulli V, Castagnaro M, Goldschmidt MH. A retrospective study of those histopathologic parameters predictive of invasion of the lymphatic system by canine mammary carcinomas. Vet Pathol 2012; 49: 330-340.

Histological subtype - Epithelial

These subtypes include those of the proposed histological classification by Goldschmidt et al (2011).

Rasotto et al (2017) reported on a prospective study that examined that prognosis of differing subtypes as outlined by Goldschmidt et al (2011). A diagnosis of carcinoma was based on pleuristratification (>3 cells thick), necrosis, marked nuclear pleomorphism or more than 3 mitoses p10HPF

Carcinoma In situ

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
16
2

Carcinoma simple

Tubular
#
dead
6mths
12 mths
24 mths
Bostock (1975)
88
85
79
Rasotto et al (2017)
15
93
73
Seung et al (2021)
91
88
Tubulopapillary
#
dead
6mths
12 mths
24 mths
Rasotto et al (2017)
12
75
67
Seung et al (2021)
 
85
75

 

Papillary intraductal
#
dead
6mths
12 mths
24 mths
Bostock (1975)
34
85
79
Rasotto et al (2017)
12
83
50

 

cystic papillary
cribriform
 

Carcinoma - solid

#
dead
6mths
12 mths
24 mths
Bostock (1975)
64
50
29
Hellman et al (1993)
52
19
45%
30
10
Yoshimura et al (2015)
23
Rasotto et al (2017)
20
45
25
Seung et al (2021)
43
21

 

Carcinomas with a solid appearance can be comprised of cells with different phenotypes. Some are combinations of epithelium and myoepithelium (identified by staining for p63), neuroendocrine cells (chromogranin, synaptophysin), and basaloid cells (CK14). They are thus potentially a heterogeneous population.

Nakagaki KYR, Nunes MM, Garcia APV, Nune FC, Schmitt F, Cassali GD. Solid carcinoma of the canine mammary gland: a histological type or tumour cell arrangement. J Comp Path 2022; 190: 1-12.

Yoshimura et al (2015) examined solid carcinomas and separated them into true solid carcinomas, malignant myoepithelioma and biphasic or complex carcinoma using CK-8 (for carcinoma), p63 and SMA for myoepithelial differentation and found a prognostic difference. 14 of 23 true solid carcinomas were infiltrative, 16/23 had vascular invation and 9/23 had lymph node invasion.

Yoshimura H, Nakahira R, Kishimoto TE, Michishita M, Ohkusu-Tsukada K, Takahashi K. Differences in indicators of malignancy between luminal epithelial cell type and myoepithelial cell type of simple solid carcinoma in the canine mammary gland. Vet Pathol. 2014; 51: 1090-1095.

Comedocarcinoma

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
7
5
Rasotto et al (2017)
17
71
29
Seung et al (2021)
20%
10%

Carcinoma - anaplastic

#
dead
6mths
12 mths
24 mths
Bostock (1975)
41
27
24
Rasotto et al (2017)
18
0
0
Seung et al (2021)
0
0

 

Carcinoma arising in a complex adenoma

Carcinoma arising in a mixed mammary tumor

Carcinoma - mixed (carcinoma with benign mesenchymal including bone)

Carcinoma - complex (carcinoma with myoepithelial component)

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
11
2
Rasotto et al (2017)
23
23
23
22
Seung et al (2021)
98
82

Yoshimura et al (2015) examined solid carcinomas and separated them into true solid carcinomas, malignant myoepithelioma and biphasic or complex carcinoma using CK-8 (for carcinoma), p63 and SMA for myoepithelial differentation and found a prognostic difference. 6 of 38 were infiltrative, 1/38 had vascular invasion and 1/38 had lymph node metastases.

Carcinoma and malignant myoepithelioma

#
dead
6mths
12 mths
24 mths
 
Rasotto et al (2017)
20
70
55
Alonso-Diez et al (2019)
13
1

 

Adenosquamous carcinoma

#
dead
6mths
12 mths
24 mths
 
Rasotto et al (2017)
10
60
0
Seung et al (2021)
0
0
 

Carcinoma with sebaceous differentiation

Chang et al (2007) reported on a dog with invasive ductal carcinoma and a region of sebaceous carcinoma. There were intravascular emboli.

Grandi et al (2011) reported finding mammary tumors with sebaceous differentiation. The cells were oil red o positive

 

Chang S-C, Liao J-W, Wong M-L; Lai Y-S, Liu C-I. Mammary Carcinoma with Sebaceous Differentiation in a Dog. Vet Pathol 2007; 44: 525-527.

Glycogen rich carcinoma

Glycogen rich carcinoma is a very rare type of mammary epithelial neoplasia. It is a clear cell type - composed of cells with distended cytoplasm that contains glycogen only.

In the report by Miscatello, there was lymph node metastases.

 

Muscatello LV, Papa V, Millanta F, Sarli G, Bacci B, Cenacchi G, Poli A, Giudice C, Brunetti B. Canine Mammary Carcinoma With Vacuolated Cytoplasm: Glycogen-Rich Carcinoma, a Histological Type Distinct From Lipid-Rich Carcinoma. Vet Pathol. 2021; 58: 63-70.

 

Lipid-rich carcinoma

Lipid rich carcinoma is a very rare type of mammary epithelial neoplasia. It is a type of mammary adenocarcinoma where the cells contain lipid vacuoles but no active lipid secretion.

Espinosa de los Monteros et al (2003) reported on 7 cases of lipid rich carcinoma. 5 had metastasis. The tumors were usually well circumscribed.

Pérez-Martínez et al (2005) reported on 2 cases of this entity. There were no clinical details.

Tei et al (2012) reported finding a dog with lipid rich carcinoma with extensive amyloid. It had metastases in the lymph node.

Mascatello et al (2021) reported 8 cases - one was a male. Peripheral invasion was not indicated. 2 had lymphovascular invasion, one of which also had systemic metastases. 2 had systemic metastases. 4 dogs survived 3, 17, 18 and 24 months.

 

Espinosa de los Monteros A, Hellmén E, Ramírez GA, Herráez P, Rodríguez F, Ordás J, Millán Y, Lara A, Martín de las Mulas J. Lipid-rich carcinomas of the mammary gland in seven dogs: clinicopathologic and immunohistochemical features. Vet Pathol. 2003; 40: 718-723.

Pérez-Martínez C1, García-Iglesias MJ, Durán-Navarrete AJ, Espinosa-Alvarez J, García-Fernández RA, Lorenzana-Robles N, Fernández-Pérez S, García-Marín JF. Histopathological and immunohistochemical characteristics of two canine lipid-rich mammary carcinomas. J Vet Med A Physiol Pathol Clin Med 2005; 52: 61-66.

Muscatello LV, Papa V, Millanta F, Sarli G, Bacci B, Cenacchi G, Poli A, Giudice C, Brunetti B. Canine Mammary Carcinoma With Vacuolated Cytoplasm: Glycogen-Rich Carcinoma, a Histological Type Distinct From Lipid-Rich Carcinoma. Vet Pathol. 2021; 58: 63-70.

 
 

Inflammatory carcinoma

Inflammatory carcinoma is not a specific subtype of mammary carcinoma, but rather a clinical presentation of invasive carcinoma with lymphatic emboli and obstruction resulting in a swollen gland that resembles mastitis. It does not refer to the presence of immune or inflammatory cells in a carcinoma.

Marconato et al (2009) reported on 43 cases. They had dermal lymphatic invasion. 81% had distant metastasis and 5% had local metastasis. 91% had progressive disease - the overall survival time was 60 days (up to 300 days). This is similar to the survival time of dogs with intravascular emboli (as above)

Clementea et al (2010) reported on 39 dogs with this type. They had a different pattern of distant metastasis - including to bladder and reproductive tract, but not to bone and less frequently to lungs, liver and kidney.

Marconato L, Romanelli G, Stefanello D, Giacoboni C, Bonfanti U, Bettini G, Finotello R, Verganti S, Valenti P, Ciaramella L, Zini E. Prognostic factors for dogs with mammary inflammatory carcinoma: 43 cases (2003–2008). J Amer Vet Med Assoc 2009; 235: 967-972

Malignant myoepithelioma

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
2
0
Alonso-Diez et al (2019)
43
3
85

Yoshimura et al (2015) examined solid carcinomas and separated them into true solid carcinomas, malignant myoepithelioma and biphasic or complex carcinoma using CK-8 (for carcinoma), p63 and SMA for myoepithelial differentation and found a prognostic difference. 3 of 11 were infiltrative, 2/11 had vascular invasion and 0/11 had lymph node metastases.

Micropapillary Carcinoma - micropapillary invasive

Rasotto et al (2012) used lymphatic invasion and lymph node metastasis as the indicators of a poor prognosis and found that a micropapillary pattern were predictive, as was peripheral invasion.

Mucinous carcinoma

Neuroendocrine carcinoma

Nakahira et al (2015) reported on 1 case. It was positive for cytokeratin (CK) 20, chromogranin A, neuron-specific enolase, synaptophysin and oestrogen receptor-b. The dog died of other causes 19 months later.

 

Nakahira R, Michishita M, Yoshimura H, Hatakeyama H, Takahashi K. Neuroendocrine carcinoma of the mammary gland in a dog. J Comp Pathol 2015; 152: 188-191.

Secretory carcinoma

Secretory carcinoma is a very rare type of mammary epithelial neoplasia. It is defined by the presence of intracellular and extracellular PAS positive secretion. The secretion is neither solely glycogen or lipid.

Cassali et al (1999) reported on a case in a 3 year old GSD. It had peripheral invasion and had pulmonary metastases.

 

 

Cassali GD, Gobbi H, Gartner F, Schmitt FC. Secretory carcinoma of the canine mammary gland. Vet Pathol. 1999 Nov;36(6):601-3. doi: 10.1354/vp.36-6-601. PMID: 10568441.

Muscatello LV, Papa V, Millanta F, Sarli G, Bacci B, Cenacchi G, Poli A, Giudice C, Brunetti B. Canine Mammary Carcinoma With Vacuolated Cytoplasm: Glycogen-Rich Carcinoma, a Histological Type Distinct From Lipid-Rich Carcinoma. Vet Pathol. 2021 Jan;58(1):63-70.

Squamous cell carcinoma

Sassi et al (2008) reported on 18 mammary carcinomas with squamous differentiation. They called 15 metaplastic carcinomas (mammary carcinoma with squamous differentiation, and 2 were called squamous cell carcinoma. Mammary and glandular squamous cells were panCK+ and CK19-. No followup data was provided.

 

Sassi F, Sarli G, Brunett Bi, Morandi F, Benazzi C. Immunohistochemical characterization of mammary squamous cell carcinoma of the dog. J Vet Diagn Invest 2008; 20: 766-773.

Sarcoma - general

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
18
 
45%
30%
10%

Sarcoma - osteosarcoma

#
dead
6mths
12 mths
24 mths
Median
Hellman et al (1993)
4
4
Langenbach et al (1998)
108
90dys

Sarcoma -chondrosarcoma

Sarcoma - fibrosarcoma

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
13
9
Alonso-Diez et al (2019)
1

Sarcoma hemangiosarcoma

Sarcomas - other

Carcinosarcoma - malignant mixed mammary tumor

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
4
2
Rasotto et al (2017)
8
0
0
Seung et al (2021)
0%
0%

References

Bostock DE. The prognosis following the surgical excision of canine mammary neoplasms. Eur J Cancer. 1975; 11: 389-396.

de Araújo MR, Campos LC, Ferreira E, Cassali GD. Quantitation of the Regional Lymph Node Metastatic Burden and Prognosis in Malignant Mammary Tumors of Dogs. J Vet Intern Med. 2015: 29: 1360-1367.

 

Clementea M, Pérez-Alenzaa MD, Peña L. Metastasis of Canine Inflammatory versus Non-Inflammatory Mammary Tumours. Journal of Comparative Pathology 2010; 143: 157-163

Diessler ME, Castellano MC, Portiansky EL, Burns S, Idiart JR. Canine mammary carcinomas: influence of histological grade, vascular invasion, proliferation, microvessel density and VEGFR2 expression on lymph node status and survival time. Vet Comp Oncol 2017: 17: 450

 

Grandi F, Salgado BS, Rocha RM. Mammary Tumors With Sebaceous Differentiation in Dogs. 2011; 48: 1002-1003.

Goldschmidt M, Peña L, Rasotto R, Zappulli V. Classification and grading of canine mammary tumors. Vet Pathol. 2011 Jan;48(1):117-31.

Hellmén E, Bergström R, Holmberg L, Spångberg IB, Hansson K, Lindgren A. Prognostic factors in canine mammary tumors: a multivariate study of 202 consecutive cases. Vet Pathol. 1993; 30: 20-27.

Langenbach A, Anderson MA, Dambach DM, Sorenmo KU, Shofe F. Extraskeletal osteosarcomas in dogs: a retrospective study of 169 cases (1986-1996)

 

 

Peña L, De Andrés PJ, Clemente M, Cuesta P, Pérez-Alenza MD. Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up: relationship with clinical and histological characteristics. Vet Pathol. 2013; 50: 94-105.

Peña L, Gama A, Goldschmidt MH, Abadie J, Benazzi C, Castagnaro M, Díez L, Gärtner F, Hellmén E, Kiupel M, Millán Y, Miller MA, Nguyen F, Poli A, Sarli G, Zappulli V, de las Mulas JM. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry. Vet Pathol. 2014; 51: 127-145.

 

Rasotto R, Zappulli V, Castagnaro M, Goldschmidt MH. A retrospective study of those histopathologic parameters predictive of invasion of the lymphatic system by canine mammary carcinomas. Vet Pathol 2012; 49: 330-340.

Rasotto R, Berlato D, Goldschmidt MH, Zappulli V. Prognostic Significance of Canine Mammary Tumor Histologic Subtypes: An Observational Cohort Study of 229 Cases. Vet Pathol. 2017 Jul;54(4):571-578.

Seung BJ, Cho SH, Kim SH, Bae MK, Lim HY, Kwak SW, Sur JH. Impact of Histological Subtype on Survival in Canine Mammary Carcinomas: a Retrospective Analysis of 155 Cases. J Comp Pathol. 2021; 186: 23-30.

Szczubiał M, Łopuszynski W. Prognostic value of regional lymph node status in canine mammary carcinomas. Vet Comp Oncol. 2011; 9: 296-303.

Tei M, Uchida K, Chambers JK, Harada H, Takahashi M, Nishimura R, Watanabe M, Nakayama H. Mammary lipid-rich carcinoma with extensive amyloid deposition in a dog. J Vet Med Sci. 2012; 74: 809-811.

Yoshimura H, Nakahira R, Kishimoto TE, Michishita M, Ohkusu-Tsukada K, Takahashi K. Differences in indicators of malignancy between luminal epithelial cell type and myoepithelial cell type of simple solid carcinoma in the canine mammary gland. Vet Pathol. 2014; 51: 1090-1095.20458


Histological grade

The grading schemes in use for mammary carcinomas are based on a human scheme.

A. Tubule Formation Points

1 >75%
2 10%–75%
3 <10%

B. Nuclear Pleomorphism

1 Uniform small nucleus
2 Moderate variation in nuclear size and shape
3 Marked variation in nuclear size

C. Mitoses per 10 HPF

1 0–9 mitoses/10 HPF
2 10–19 mitoses/10 HPF
3 20 mitoses/10 HPF

3–5 I (low, well differentiated) - all alive at 24 and 40 months
6–7 II (intermediate, moderately differentiated) - 80% alive at 24 and 40 months
8–9 III (high, poorly differentiated) - 30% alive at 24 and 40 months

Grade I
#
dead
6mths
12 mths
2yrs
Pena et al 2014
100
Karayannopoulou et al 2011
100
Rasotto et al (2017)
86
81
69
Grade II
#
dead
6mths
12 mths
2yrs
Pena et al 2014
80
Karayannopoulou et al 2011
55
Rasotto et al (2017)
23
96
78
Grade III
#
dead
6mths
12 mths
2yrs
Pena et al 2014
30
Karayannopoulou et al 2011
10
Rasotto et al (2017)
60
27
0

Peña L, De Andrés PJ, Clemente M, Cuesta P, Pérez-Alenza MD. Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up: relationship with clinical and histological characteristics. Vet Pathol. 2013; 50: 94-105.

Karayannopoulou M, Kaldrymidou E, Constantinidis TC, Dessiris A. Histological grading and prognosis in dogs with mammary carcinomas: application of a human grading method. J Comp Pathol 2005 Nov;133(4):246-52.

Rasotto R, Berlato D, Goldschmidt MH, Zappulli V. Prognostic Significance of Canine Mammary Tumor Histologic Subtypes: An Observational Cohort Study of 229 Cases. Vet Pathol 2017 Jul;54(4):571-578.

Hormone receptor expression

The general classification using the hormone receptors estrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER2), and basal like (p63, SMA, vimentin) is

Luminal A ER+, HER2- (humans receive Tamoxifen, 90% 10 yr survival)

Luminal B ER+, HER2+ (Humans with high Ki67 are more agressive, receive Tamoxifen and anthracycline/Taxol)

HER2 overexpressing ER-, HER2+ (humans receive Herceptin, a monoclonal antibody to HER2/neu

Basal-like ER-, HER2- p63+, SMA+, Vimentin + (humans receive anthracycline/Taxol)

normal - all negative

General consensis statement suggests using staining in 10% or more of cells to be regarded as positive. Use of the published recommendations for each receptor is advised. Outcome based assessment would be most welcome!

Peña L, Gama A, Goldschmidt MH, Abadie J, Benazzi C, Castagnaro M, Díez L, Gärtner F, Hellmén E, Kiupel M, Millán Y, Miller MA, Nguyen F, Poli A, Sarli G, Zappulli V, de las Mulas JM. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry. Vet Pathol. 2014; 51: 127-145.

 

Other prognostic factors

Prolactin concentration

Queiroga et al (2014) found that tissue and serum concentration of prolactin was higher in the more malignant types of mammary tumors, and were highest in inflammatory mammary carcinoma.

Queiroga FL, Pérez-Alenza MD, González Gil A, Silvan G, Peña L, Illera JC. (2014) Serum and tissue prolactin levels in canine mammary tumours including inflammatory mammary carcinomas: insights into clinical and prognostic implications. Vet Rec 2014; 175: 403-4

 

 

Immunohistochemistry of mammary tumours.
Normal mammary gland

 

 

Mammary carcinoma

The majority of canine mammary tumours are complex tumours with both epithelial and myoepithelial proliferative components. These arise from a progenitor cell and differentiate to either epithelium or myoepithelium. Using immunohistochemistry for cytokeratin (CK) 8/18, CK5, CK14, a-smooth muscle actin (SMA), calponin (CALP),
p63 and vimentin (VIM), Rasotto et al (2014) found that in normal mammary glands the luminal epithelial cells stain for CK 8/18 only but that ductal epithelial cells stain for all cytokeratins. The basal (progenitor) myoepithelial cells were CK5+, CK14+, p63+ and VIM+, and the myoepithelium was CALP+, SMA+ and VIM+. In simple carcinomas, the neoplastic cells stained for all cytokeratins and nothing else. In the complex carcinomas and the carcinoma and malignant myoepithelioma group, the epithelial component stained with all cytokeratins and rarely with vimentin. The myoepithelial component stained in an identical fashion for basal myoepithelial cells. In carcinosarcomas, the epithelial component stained only for cytokeratins and the mesenchymal component only stained with vimentin and not with myoepithelial markers.

to R, Goldschmidt MH, Castagnaro M, Carnier P, Caliari D, Zappulli V. (2014) The Dog as a natural animal model for study of the mammary myoepithelial basal cell lineage and its role in mammary carcinogenesis. J Comp Path 2014; 151: 166-180.

Unusual types of mammary neoplasia

Mammary oncocytoma

Nagahara et al (2016) reported on minute and solitary mammary tumors with the histological classification of oncocytoma. They had cells with a distended cytoplasm with a granular or swollen appearance. They contained many mitochondria so mee the criteria of an oncocytoma. They had neuroendocrine differentiation.

 

Nagahara R, Kimura M, Itahashi M, Sugahara G, Kawashima M, Murayama H, Yoshida T, Shibutani M. Canine mammary minute oncocytomas with neuroendocrine differentiation associated with multifocal acinar cell oncocytic metaplasia. J Vet Diagn Invest. 2016 Nov;28(6):722-728.

 

References

 

Sleeckx N, de Rooster H, Veldhuis Kroeze EJ, Van Ginneken C, Van Brantegem L.Canine mammary tumours, an overview. Reprod Domest Anim 2011; 46: 1112-1131.

Mammary disease in Male dogs

It is rare to have mammary disease in male dogs.

Mammary Neoplasia

Neoplasia of the mammae in dogs is rare.

Saba et al (2007) reported on 8 dogs. 7 had adenomas (1 simple adenoma, 4 complex adenomas, 2 benign mixed mammary tumours) and one squamous cell carcinoma (and papillary adenoma). None were metastatic.

Bearss et al (2012) reported on 27 tumors in 18 male dogs. 26 were adenomas with a mixed papillary and tubular pattern. 5 had multiple tumors. 17 were tubular (they said acinar) and 1 was complex. No dog died of mammary disease.

Silva et al (2019) described a male dog with inflammatory carcinoma. The survival time was 35 days.

Machado et al (2020) reported on 2 dogs with mammary adenocarcinomas - one tubulopapillary and one arising in a complex adenoma.

 

Bearss JJ, Schulman FY, Carter D. Histologic, immunohistochemical, and clinical features of 27 mammary tumors in 18 male dogs. Vet Pathol. 2012; 49: 602-607.

Silva DMD, Kluthcovsky LC, Jensen de Morais H, Pallú GM, Dos Santos GC, Costa Castro JL, Engracia Filho JR. Inflammatory Mammary Carcinoma in a Male Dog-Case Report. Top Companion Anim Med. 2019; 37: 100357.

Saba CF, Rogers KS, Newman SJ, Mauldin GE, Vail DM. Mammary gland tumors in male dogs. J Vet Intern Med. 2007; 21: 1056-1059.

Machado MCA, Ocarino NM, Serakides R, Moroz LR, Sementilli A, Damasceno KA, Cruz CH, Estrela-Lima A. Triple-negative mammary carcinoma in two male dogs. J Vet Diagn Invest. 2020; 32: 94-98.