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

 

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. 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.

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.

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 in response to infection.

Mammary infections occur early in lactation or pseudopregnancy.  Staphylococci, streptococci and  E. coli are the major isolates.  Infection of fissures in nipples and adjacent skin spreads via the ducts and lymphatics into the gland with abscesses and/or purulent 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..

Inflammation and neoplasia are sometimes linked, as lymphocytes, plasma cells and other cells may be present. Obstruction and rupture of ducts secondary to neoplasia can produce inflammation. This is not typically called a primary mastitis.  Some are confused with inflammatory carcinoma. The diagnosis of inflammatory carcinoma was firstly made in women, and it 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 which causes swelling and erythema or even limb swelling.  The initial clinical diagnosis is often mastitis and not neoplasia.

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.

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 clinical 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                          0 8%
after 2nd estrus                       26%
late ovariectomy has some protective effect

 

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

Classification

There are many 'classification' papers ourlining 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 as follows (from Goldschmidt et al 2011)

  1. Malignant epithelial neoplasms
    1. Cacrinoma - in situ
    2. Carcinoma - simple
      1. tubular
      2. tubulopapillary
      3. cystic papillary
      4. Cribriform
    3. Carcinoma - micropapillary invasive
    4. Carcinoma - solid
    5. Comedocarcinoma
    6. Carcinoma - anaplastic
    7. Carcinoma arising in a complex adenoma
    8. Carcinoma - complex type
    9. Carcinoma and malignant myoepithelioma
    10. Carcinoma - mixed type (with cartilage and bone)
    11. Ductal carcinoma
    12. Intraductal papillary carcinoma
  2. Malignant epithelial neoplasms - special types
    1. Squamous cell carcinoma
    2. Adenosquamous carcinoma
    3. Mucinous carcinoma
    4. Lipid rich carcinoma
    5. Spindle cell carcinoma
    6. Inflammatory carcinoma
  3. Malignant mesenchymal neoplasms - sarcomas
    1. Osteosarcoma
    2. Chondrosarcoma
    3. Fibrosarcoma
    4. Hemangiosarcoma
    5. others
  4. Carcinosarcoma - malignant mixed mammary tumor
  5. Benign neoplasms
    1. Adenoma - simple
    2. Intraductal papillary adenoma
    3. Ductal adenoma (basaloid)
    4. Fibroadenoma
    5. Myoepithelioma
    6. Complex adenoma
    7. Benign mixed tumor
  6. Hyperplasia/dysplasia
    1. Duct ectasia
    2. Lobular hyperplasia
    3. Epitheliosis
    4. Papillomatosis
    5. Fibroadenomatous change
    6. Gynecomastia
  7. Neoplasms of the papilla
    1. Adenoma
    2. Carcinoma
    3. Carcinoma with epithelial infiltration (Pagets)
  8. Hyperplasia/dysplasia of the papilla
    1. melanosis of skin of papilla

These and other types are indicated below in Prognosis

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

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.

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
   

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

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

These subtypes include those 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

Tubulopapillary

#
dead
6mths
12 mths
24 mths
Rasotto et al (2017)
12
75
67
 

 

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

 

cystic papillary
cribriform

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..

 

 

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.

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

 

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

Carcinoma - anaplastic

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

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

 

 

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.

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 oiil red o positive

Lipid-rich carcinoma

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.

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.

 

Adenosquamous carcinoma

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

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.

Malignant myoepithelioma (Spindle cell carcinoma, squamous cell carcinoma - spindle cell variant, carcinoma spindle cell variant)

#
dead
6mths
12 mths
24 mths
Hellman et al (1993)
2
0

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.

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

 

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

 

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.

 

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.

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

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.

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)

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

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.

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.

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.

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.

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.

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.

 

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.