Disease of the Mammae of Cats

Rob Foster

University of Guelph

Mastitis

 

Mammary Masses - non neoplastic

Cystic dilation of mammary ducts

Duct hyperplasia

Lobular hyperplasia

Epithelial hyperplasia

Adenosis

Fibroadenomatous change (feline mammary hyperplasia, fibroepithelial hypertrophy, mammary hypertrophy)

Fibroadenomatous hyperplasia (mammary hypertrophy) is highly prevalent and is the most common disease of the gland; it occurs in young intact queens. Queens less than 2 years old are most likely to develop mammary enlargement, which usually occurs in the spring and with the first several estrous cycles. Much of what is known about this disease is based on its coinciding with the luteal phase of estrus, early in pregnancy, or after progestin therapy. High concentrations of progesterone or progesterone-like substances are the common link. As expected, progestogen treatment of an old neutered male or female can also induce this lesion. What is difficult to explain is the distribution of the lesion, as all mammae, only one mamma, or one mammary gland may be affected. The lesion is proliferation of mammary ducts and adjacent stroma. This overstimulation of an otherwise normal process is the result of a dysregulation of tissue growth with the stimulation of receptors by progesterone. Some have theorized an exaggerated response to prolactin as well. Hemorrhages, coagulative necrosis, and/or ulceration of affected areas can occur. In young queens, resolution is spontaneous or ovariohysterectomy is effective. Older neutered queens on a progestogen require drug withdrawal and sometimes mastectomy.

 

 

Mammary Neoplasia

Benign

Adenomas - Simple and complex

Fibroadenoma

Benign mixed tumor

Duct papilloma

 

 

Mammary Carcinoma

Pathogenesis of mammary neoplasia

As with most neoplasms, cancer stem cells are identified in feline mammary carcinomas and in particular, in cell lines by demonstrating expression of CD 133 (Pang et al 2013).

Prognosis

Zappulli et al (2015) provides a comprehensive and critical review of the literature of mammary carcinomas in cats with a focus on prognostic factors. They highlight the inherent difficulties of comparing different studies and on the lack of use of clinical outcome as the definitive endpoint of prognostic studies.

Zappulli V, Rasotto R, Caliari D, Mainenti M, Peña L, Goldschmidt MH, Kiupel M. Prognostic evaluation of feline mammary carcinomas: a review of the literature. Vet Pathol. 2015; 52: 46-60.

Size

MacEwen et al (1984) found that size was a major determinant of prognosis expecially those above 28 sq cm or about 3 cm diameter. Those >28cm2 had a survival of about 6 months. in their study. Radical mastectomy was no different to simple lumpectomy for long term survival, but improved disease free interval.

Seixas et al (2011) found that size was related to grade, and that grade 3 tumors tended to be larger than grade 2 tumors which were larger than grade 1 tumors. There was great variation in the size of tumors at each grade.

In their review on prognostic factors, Zappulli et al (2015) found that the range was as follows:

Take home message: if the mammary tumour is greater than 3 cm expected survival is less than six months otherwise the range is very broad!

Lymph node metastasis

Seixas et al (2011) found an association between survival and lymph node metastasis. Only 25% metastasised to the lymph node and those with lymph node metastasis did not survive past 9 months. The majority did not have lymph node metastasis however. Life expectancy if there is lymph node metastasis is a median of five months.

Mills et al 92015) found that the median survival was 9 months.

Take home message: if the mammary tumour has metastasised to the lymph node, it has already demonstrated metastatic potential in the life expectancy is short – less than five months.

Lymphatic invasion

Seixas et al (2011) found that lymphatic invasion was a significant prognostic factor. Of those with lymphatic invasion, 50% of cats survived 6 months, 20% for 12 months and 10% for 24 months.

Mills et al (2014) found that in their 97 cats, 40 had lymphovascular invasion. Median survival was 8 months. Median survival for those with no invasion was 18 months

Take-home message: if there is lymphatic invasion, it is a poor prognostic indicator in the life expectancy is short with only 20% surviving for one year, and a median survival of 8 months.

Grade

There are 2 publications I use that provide clinical followup.

Seixa et al (2011)

They used a modification of the original Elston and Ellis (Nottingham Grading System) grading scheme for Human Breast cancer by using different mitotic rates than the original (which was 0-8, 9-16 and 17+ p10HPF)

   
Tubule formation >75%
1
10-75%
2
<10%
3
Nuclear pleomorphism uniform small cells
1
moderate nuclear size and variation
2
Marked variation
3
Mitoses 0-5 p10HPF
1
6-10 p10HPF
2
>10 p10HPF
3

Grade 1 = 3-5 - 24 months survival 100%

Grade 2 = 6-7 - 24 month survival 40%

Grade 3 = 8-9 -24 month survival 2%

Seixa et al (2011) found that grade was an independent prognostic factor. In a study of 92 cats with invasive carcinoma, 5 were grade 1, 43 were grade 2 and 44 were grade 3. Grade I tumors were in the younger cats and were smaller (<2cm). Grade II tumors were intermediate sized tumors (2-3cm) and grade III tumors were larger (>3cm) and more likely to be micropapillary in type. The 2 year median survival was Grade 1, 3 of 4; Grade II, 7 of 27 (33%), and Grade III, 1 of 32 (3%).

Mills et al (2014)

Mills et al (2015) evaluated the 108 carcinomas in 97 cats for which they had followup. They compared the original Elston and Ellis method with a modified scheme and devised their own scheme. Their own was superior!

It was

    Score
Lymphovascular invasion Absent 0
  Present 1
Nuclear form <5% abnormal 0
  >5% abnormal 1
Mitotic count <62 0
  >62 1
Score 0 Grade I Median 31 months, survival at 18 months 82%
Score 1 Grade II Median 14, 37% at 18 months
Score 2-3 Grade III median 8, survival at 18 months 18%

 

Take-home message: grade is a reliable indicator, especially identifying grade I and III and those that are grade 3 tumours have a very poor prognosis

 

Mills SW, Musil KM, Davies JL, Hendrick S, Duncan C, Jackson ML, Kidney B, Philibert H, Wobeser BK, Simko E. Prognostic Value of Histologic Grading for Feline Mammary Carcinoma: A Retrospective Survival Analysis. Vet Pathol. Vet Pathol. 2015; 52: 238-249.

Seixas F, Palmeira C, Pires MA, Bento MJ, Lopes C. (2011) Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J. 2011; 187: 65-71.

Classification (WHO)

 
Non infiltrating (in situ) carcinoma
Tubulopapillary

Seixas et al (2011) found that cats with tubulopapillary or complex carcinomas survived the longest.

Mills et al (2014) found that cats with this type had a median survival of 21 months.

Solid

Mills et al (2014) found that cats with this type had a median survival of 10 months.

Ductal carcinoma (rather than complex carcinoma)

densly cellular, well defined and multinodular often within ectatic ducts

Luminal cells are panCK and CK8 and 18 only

Basal/myoepithelial are panCK+ Ck 5 and 6, CK14, p63, cim, CALP, SMA

Seixas et al (2011) found that cats with tubulopapillary or complex carcinomas survived the longest.

Zappulli V, Caliari D, Rasotto R, Ferro S, Castagnaro M, Goldschmidt M. Proposed classification of the feline "complex" mammary tumors as ductal and intraductal papillary mammary tumors. Vet Pathol. 2013; 50: 1070-1077

Intraductal papillary carcinoma

Multinodular papillary within ectactic ducts and papillae have a fibrous stalk

Zappulli V, Caliari D, Rasotto R, Ferro S, Castagnaro M, Goldschmidt M. Proposed classification of the feline "complex" mammary tumors as ductal and intraductal papillary mammary tumors. Vet Pathol. 2013; 50: 1070-1077

Cribriform

Mills et al (2014) found that cats with this type had a median survival of 8 months.

Squamous cell carcinoma

Mills et al (2014) found that cats with this type were too rare to have survival data. If there was >5% squamous differeintiation, the median survival was 12 months

Mucinous carcinoma
Carcinosarcoma
Carcinoma or sarcoma in benign tumor
 

Nuclear pleomorphism

Nuclear pleomorphism is the variability in size, shape and staining characteristics of nuclei. It really refers to volume of nuclei.

De Vico and Maiolino (1997) studied 2 dimensional features of the nuclei of cells of mammary carcinoma and found that anisokaryosis, nuclear area, and nuclear shape not correlated with prognosis, but variations in these did such that when the variation is greater, survival in in solid and tubular adenocarcinomas was <1 yr.

De Vico G, Maiolino P. (1997) Prognostic value of nuclear morphometry in feline mammary carcinomas. J Comp Pathol 1997; 117: 99-105.

Proliferation markers

Mitotic count

Mitotic count is an prognostic variable and it is part of the grading scheme for mammary carcinomas

Ki67

Soares et al (2016) determined that 14% of cells Ki67 positive was the cutoff for those that should be benign and those with a high risk of spread.

 

Soares M, Ribeiro R, Carvalho S, Peleteiro M, Correia J, Ferreira F. Ki-67 as a Prognostic Factor in Feline Mammary Carcinoma: What Is the Optimal Cutoff Value? Vet Pathol. 2016; 53: 37-43

Molecular markers

Claudins

Claudin one and seven was investigated in mammary carcinomas and there was an inverse relationship between expression of Claudin 7 and grade of tumour.

 

 

 

General References

Giménez F, Hecht S, Craig LE, Legendre AM. (2010) Early detection, aggressive therapy: optimizing the management of feline mammary masses. J Feline Med Surg. 2010; 12: 214-224

Hughes K, Dobson JM. (2012) Prognostic histopathological and molecular markers in feline mammary neoplasia. Vet J. 2012; 194: 19-26.

MacEwen EG, Hayes AA, Harvey HJ, Patnaik AK, Mooney S, Passe S. Prognostic factors for feline mammary tumors. J Am Vet Med Assoc 1984; 185: 201-204.

Matos AJ, Baptista CS, Gärtner MF, Rutteman GR. (2012) Prognostic studies of canine and feline mammary tumours: the need for standardized procedures. Vet J. 2012; 193: 24-31.

Peñafiel-Verdu C1, Buendia AJ, Navarro JA, Ramirez GA, Vilafranca M, Altimira J, Sanchez J.Reduced expression of E-cadherin and β-catenin and high expression of basal cytokeratins in feline mammary carcinomas with regional metastasis. Vet Pathol 2012; 49(6): 979-987.

Pang LY, Blacking TM, Else RW, Sherman A, Sang HM, Whitelaw BA, Hupp TR, Argyle DJ. (2013). Feline mammary carcinoma stem cells are tumorigenic, radioresistant, chemoresistant and defective in activation of the ATM/p53 DNA damage pathway. Vet J. 2013; 196(3): 414-423.

Rute Flores A, Rema A, Carvalho F, Lopes G, Faustino A, Dias Pereira P. (2014) Clinicopathological Significance of Immunoexpression of Claudin-1 and Claudin-7 in Feline Mammary Carcinomas. J Comp Path 2014; 151: 339-346

Seixas F, Palmeira C, Pires MA, Bento MJ, Lopes C. (2011) Grade is an independent prognostic factor for feline mammary carcinomas: a clinicopathological and survival analysis. Vet J. 2011; 187: 65-71.