Pathol Vet 1970 Moulton 289 320

http://vet.sagepub.com/Online

Pathologia Veterinaria

http://vet.sagepub.com/content/7/4/289The online version of this article can be found at:

DOI: 10.1177/030098587000700401

1970 7: 289Pathol VetJ. E. Moulton, D. O. N. Taylor, C. R. Dorn and A. C. Andersen

Canine Mammary Tumors

Published by:

http://www.sagepublications.com

On behalf of:

College of Veterinary Pathologists.American College of Veterinary Pathologists, European College of Veterinary Pathologists, & the Japanese

can be found at:Pathologia Veterinaria OnlineAdditional services and information for

http://vet.sagepub.com/cgi/alertsEmail Alerts:

http://vet.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

What is This?

- Jul 1, 1970Version of Record >>

by guest on May 10, 2013vet.sagepub.comDownloaded from

http://vet.sagepub.com/

http://vet.sagepub.com/content/7/4/289

http://www.sagepublications.com

http://vet.sagepub.com/cgi/alerts

http://vet.sagepub.com/subscriptions

http://www.sagepub.com/journalsReprints.nav

http://www.sagepub.com/journalsPermissions.nav

http://vet.sagepub.com/content/7/4/289.full.pdf

http://online.sagepub.com/site/sphelp/vorhelp.xhtml


Path. vet 7: 289-320 (1970)

From the Department of Pathology and the Radiobiology Laboratory, School of Vctcrinary Medicine, University of California, Davis, and the California State

Department of Public Health, Berkeley

Canine Mammary Tumors

J . E. MOULTON, D. O.N. TAYLOR, C. R. DORN, and A. C. RNDERSEN

Canine mammary tumors are difficult to classify because of their marked histologic complexity. The main objectives in the present study were (1) to study certain epidemiologic factors in groups of dogs with tumors from a heterogeneous population, from 2 urban counties, and from a closed colony in a life-span study, (2) to describe the pathogenesis of these tumors, and (3) to present a method of classification.

Review of the Literature

General reviews on canine mammary tumors have been presented by COT- CHINIX, MASON^", I\/ISDORPB', b10ULTON54, and M U L L I C ; A N ~ ~ . A review that relates to the present study follows.

Zmidence. Mammary tumors are among the most common tumors that appear in dogs. According to BLOOM^ they represent 25 to 30 'x of all tumors of thc bitch. 'They appeared in 38y0 of the female beagles during the first 8 years in a life-span study reported by ANDERSEN~. The figures indicating the percentage of mammary tumors among all tumors in male and female dogs vary considerably. COT CHIN'^ gives a figure of 18% for thc frcquency of mammary tumors among all tumors of dogs, D A SILVA, et a1.z'-28%, DIETZMANNe4-41%, DOBBERSTEIN and MATTH1ASz5

- lo%, I<RONBERGER47 - 12 o/ , sTICKER71 - 44%, P0PPENSIEKfi4 - 14%, and DORN, et aLz7 - 13%. Excluding the unusually high figures (over 40'2,) the average figure for frequency of mammary tumors among all tumors of dogs in both sexes is 16%). Relative frequency will indicate the likelihood of a dog having a particular type o f neoplasm, but population-at-risk denominators are required for calculation of incidence rates that indicate the risk of developing a neoplasm in the general population. The only published article containing incidence data for canine mammary neoplasia reported an annual rate of 198.8 cases per 100,000 female dogs28.



290 M O U L T O N , et al.

Canine mammary tumors have been reported in all parts of the worId21~2~~ 24. 253 42-44. 53. 5 4 , 67, but there is no indication of any geographic difference in frequency.

A g e distribrition. The age distribution of mammary tumors follows closely the age distribution of most types of tumors in dogs289 48, 60, 72. Mammary tumors are rare in dogs less than 2 years of age, but a sharp increase in the incidence of tumors begins at approximately 6 years of age28, the onset of the "cancer age". A bell-shaped curve would result from plotting the age distribution of mammary tumors. Age-specific rates of incidence which correct for the smaller population of older dogs, and thus fewer reported tumors in them, indicate a much higher risk of mammary cancer in old bitches than in young females". However, the age- specific rate of incidence does decrease after 10 to 11 years of age.

Breedsz~scepfibili~y. Most reports indicate no clear predilection as to breed when the total number of dogs of each breed for each area are considered. Exceptions are made by RISER^^ who reported that the Scottish terrier and retriever most commonly had mammary tumors and by FRYE, et a1.37 who reported a greater incidence of these tumors in the dachshund. In a subsequent analysis*[limited to malignant neoplasms which included some of the cases in the series studied by FRYE, et a1.37, there were more dachshunds than expected, but the difference was not statistically significant. A number of German workers109 ZO, 66 claim that the dachshund is the breed most common with mammary tumors.

SexGal inflaences. Mammary tumors occur almost exclusively in female dogs, but there are scattered reports of their occurrence in males also99 15. 36 , 37, 57. (;(I.

There is no evidence that castration or the occurrence of estrogen-secreting Sertoli- cell tumors of the testes have any influence on the frequency of mammary tumors in males.

Endocrinic aspects. There is strong evidence 28, 3 7 7 4 O 3 57 to support the hypo- thesis that ovariohysterectomy has a sparing effect on tumor formation, especially when performed prior to the first estrual cycle. FRYE, et a1.37 reported a 4-fold greater risk of mammary tumors in entire as compared with neutered females. More recently, SCHNEIDER, et al.70 have shown that bitches neutered prior to estrus have 0.5% of the mammary cancer risk as intact females.

It has been reported by many investigators6, 8,10. 23. 6 1 3 6 5 that mammary tumors are associated with endocrinic disorders such as irregular estrual cycle, ovarian follicular cysts, persistent corpora lutea, and hyperplastic endometrium. In contrast, BRODEY, et al.11 in a carefully conducted study of 57 dogs with mammary tumors and 244 dogs that were normal found no significant difference between the 2 groups in regularity of the estrual cycle, pseudopregnancy, or pregnancy. SCHNEIDER, et al.7"later confirmed this in a study of 93 dogs with mammary cancer.

The benign tumors are said to enlarge and become soft during proestrus, estrus, and early metestrus and then become smaller and firmer during late metestrus and anestrus8. 23. It was not clear in these reports whether these changes occurred in the mammary neoplasm or in the normal tissue surrounding the neoplasm. Profound hyperplastic and regressive changes occur in the normal canine mammary gland during the estrual cycle.

* Unpublished data.



Canine 1Mammary Tumors 291

DOZZA and COLUZZI”) found increased urinary estrogen in bitches with mammary neoplasms. ~ \ / I U L L I G A N ~ * observed enlargement of the mammary glands, but GARDNER~* found enlargement of the nipple only in bitches injected with estrogenic compounds.

There is a paucity of data on the incidence of mammary tumors in bitches that are virgins compared with bitches that have had litters. BLOOM* reported a decrease in incidence of tumors in dogs that had 1 or more litters compared with virgins. ANDERSEN~ in a life-span study of a carefully controlled colony of beagles observed no difference in the incidence of mammary tumors in virgin bitches ver- sus bitches that had 2 litters before 4 years of age. However, more recently he found a significantly lower incidence of tumors in bitches that had whelped a large number of times.

Location of mammarj tumors. There is an increasing frequency of mammary tumors from the axillary (the most cephalad of the 5 sets of glands) to the inguinal (the most caudal of the gIands)3, 34. 40, 4 2 , 43, 53, 60, 65. There is no significant difference in the mammary location of the different types of tumorsc0.

Multiple mammary tumors of the same and different histologic types have been described by many workers. BLOOM^ reported that multiple involvement occurred 50% of the time. M U L L I C A N ~ ~ . described the occurrence of 2 mixed tu-

mors in the same or different glands over 20% of the time, mixed tumor plus coexisting carcinoma in the same or another gland 5 to 10% of the time, and in- dependent carcinomas in separate mammary glands rarely. Other instanccs of multiple primary tumors have been reportedl3, 65. 73. Occasionally, malignant tumors occupy more than 1 gland due to direct extension or metastasis.

Classification of tumors b_v type. Excluding reportss, 21, 64 65 of relatively high figures for the incidence of carcinoma, the average relative frequency of carcinoma among all mammary tumors is 30%. With the exception of reportsz, 24, 4Ii, G4. e 5 , 72

with unusually low figures for incidence of mixed tumors, usually because of differences in methods of classification, the average frequency of mixed tumors is about 50%.

There are considerable variations in the classifications of canine mammary tu-

mors. There is fairly good agreement on including categories such as adenoma, carcinoma, benign and malignant mixed tumors, and osteosarcomas. However, there has been considerable variation in the use of other categories : duct papilloma has been listed as adenoma or included as a mixed tumor; fibroadenoma has been listed as a separate tumor or included among the mixed tumors; separate headings have been made for adenoma, fibroma, myxoma, chondroma, and osteoma, or they have been included as part of the mixed tumor group. Myoepithelioma has come into common use as a diagnostic term193 59. Because myoepithelioma was not recognized in the past, it was often called fibrosarcoma. Compounding names such as fibro-, adeno-, and chondro- for designating mixed tumor44 has been almost eliminated because such terminology is so cumbersome.

There is considerable variation in the reported methods of classifying the carcinomas. COT CHIN^^ subdivided them as squamous-cell carcinoma (arising from the lining of a teat canal or major duct or by metaplasiaof glandular epithelium), duct carcinoma (including solid, papillary, and adenocarcinoma with true glandular pattern), sclerosing or scirrhous carcinoma (with productive fibrous stroma), solid lobular carcinoma (consisting of solid, lumenless sheets of cells), and anaplastic




carcinoma (no glandular pattern). DOBBERSTEIN and MATT HI AS^^ classified the carcinomas as adenocarcinoma, spheroidal-cell or solid carcinoma (includes scirrhous and medullary), mucous carcinoma (a tumor with formation of mucin by the tumor cells), and squamous carcinoma. J A B A R A ~ ~ used the terms adenocarcinoma, spheroidal-cell (solid) carcinoma, and squamous carcinoma. MULLIGANS9 classified the carcinomas as duct carcinoma, non-infiltrating (papillary and solid) ; duct carcinoma, infiltrating (papillary, solid, papillary and solid, medullary, and fibrosing) ; lobular carcinoma, non-infiltrative and infiltrative ; and mixed duct and lobular carcinoma, non-infiltrating and infiltrating. M I S D O R P ~ ~ subdivided carcinomas as squamous carcinoma, duct carcinoma, adenocarcinoma (papillary, cystadeno-, alveolar-cell), solid, spheroidal-cell (alveolar-cell, clear-cell, circumscribed, and fusiform), and anaplastic carcinoma. WILL IS^^ had a classification for canine mammary tumors which included intraductal carcinoma (papillary, cribriform, lactiform, and solid), extraductal (adeno-, spheroidal, solid, and diffuse), and metaplastic (mucoid or colloid, squamous). He recognized transition from epithelial cystic hyperplasia to papilloma to carcinoma. In a recent report from the World Health Organization74 carcinomas were classified as adeno-, papillary, cribriform, cystic, papillary cystadeno-, solid, cylindromatous, spindle-cell, metaplastic, squamous-cell, mucoid, and anaplastic.

Origin of cartilage and bone in mixed tgmov. There has been controversy about the origin of cartilage and bone in mixed tumors. Three lines of thinking have developed. Some investigators’. 42 reported that the cartilage was derived from epithelial-cell metaplasia. A larger group328 33, 41, 45, G‘J reported that cartilage and bone developed from metaplasia of connective tissue. Several workers53 ‘j2 reported that epithelial cells stimulated metaplasia of stromal elements. BLOOM^ considered mixed tumors as true epithelial tumors with non-neoplastic stromal metaplasia. WILL IS^^ pointed out that cartilage could be stimulated by epithelial cells scattered in mucinous secretion, but that true cartilage or bone developed from metaplasia of stromal tissue. JACKS ON^^ agreed that some cartilage and bone developed from stromal metaplasia but that all cases were not explicable on that basis. Some workers?. 14, 19, 30, 31, 39, 59, 83 considered cartilage in mixed tumors as developing from myoepithelial cells. Normally, myoepithelial cells are arranged around the acinar epithelial cells within the limits of the epithelial basement membrane on the epithelial side of the intralobular connective tissue. In early stages of proliferation these cells are separated into a loosely arranged network due to the secretion of mucin (probably chondromucin). Then they show transition into cartilage, which according to physical characteristics41 and histochemical staining for chondroitin sulfuric acid and alkaline phosphatase129 19, 30. 31 is true hyaline cartilage. COTCHINIS

reported that the bone in these tumors arose by endochondral ossification of the cartilage formed by the myoepithelial cells or by intramembranous ossification of stromal connective tissue.

Metastasis. The percentages for metastasis of mammary tumors would be higher if the tumors were allowed to remain for the full life-span of the dog without surgical intervention. In MISDORP’s~~ study of 56 dogs with carcinomas, the lymph nodes were involved with metastases in 860/,, the lungs -72%, adrenals - 12%, kidneys - 11%, heart - 11%, liver - lo%, and bone ~ 10%. In 18 dogs with carcinoma reported by IMIJLLIGAN(~O the nodes were involved in 60%, lungs - 30%, subcutaneous tissue - 30%, liver - 20%, and spleen - 20%. In 155



Caninc hlammary Tumors 293

mammary carcinomas reported by I < R O O K ~ ~ lymph nodes were involved in 41y0, lungs - 33o/j, kidney - loyo, liver - 9y0, myocardium -5%, and other sites in less than 5%. In a series of 18 mammary carcinomas reported by COT CHIN^^ the regional nodes were involved in 72%, lungs - SO%, bone - llyo, and all other visceral organs - 22%. In a consecutive series of 85 dogs with carcinomas reported by FIDLER and BRCIDEY~~ the lungs were involved in SOY0, lymph nodes - 61%, heart - 160/,, brain - 150/,, liver and kidney - 14% each, and other sites - 11% or less. In this study the relatively high incidence of metastasis in the lungs compared with the regional (axillary or inguinal) lymph nodes suggested that tumor emboli spread from the mammary gland to the lungs by direct venous transport as well as by lymphatics. A large number of these bitches with metastases in the lungs also had metastases in the thoracic lymph nodes because of the spread from the lungs to the thoracic lymph nodes via the pulmonary lymphatics. Metastasis of carcinomas to the bones168 51, 52 would probably be reported more often if more detailed examination of the skeleton were made at necropsy.

The lymph nodes involved with metastases of carcinoma depend on which mammary glands are affected4, 34, 67. Carcinomas in the cephalad 3 (axillary, thoracic, central) mammary glands commonly metastasize first to the axillary and sternal nodes, whereas carcinomas of the caudal 2 (abdominal, inguinal) mammary glands metastasize to the superficial inguinal lymph nodes. Because of lymphatic connections between the first 3 and between the last 2 mammary glands it is common to find metastases in adjacent mammary glands.

There is not much information on metastasis of malignant mixed tumors and sarcomas. Metastases of malignant mixed neoplasms have usually appeared as carcinomas. FOREMAN35 observed metastases in the liver and spleen of a bitch with a malignant mixed tumor. FIDLER and B R o D E Y ~ ~ observed metastases in 7 dogs with malignant mixed tumors. Metastases were found in the lungs of 6, lymph nodes of 7, and other sites of 2 or less dogs. COT CHIN^^ observed metastases in 7 of 27 dogs with malignant mixed tumors. FIDLER and BRODEY:~~ observed sarcomas in 8 dogs with metastases in the lungs of 7, lymph nodes of 6, and other sites in 2 or less. COT CHIN^^ reported metastases in 5 of 23 sarcomas of mammary origin. M U L L I G A N ~ ~ reported a dog with malignant myoepithelioma that had metastases in the Iungs. COT CHIN^^ described metastases in 6 of 40 “other sarcomas of mammary origin” which were probably myoepitheliomas ; the sites of metastases were not given.

Materials and Methods

Sources ofcases. Specimens from a total of 1,366 dogs with mammary tumors from 3 different sources were studied. Among these, 803 cases were reported by practicing veterinarians in Alameda and Contra Costa counties of California from July 1963 to June 1967 to the Animal Neoplasm Registry (ANR), California State Department of Public Health26; 441 were referral cases from all over the state of California diagnosed from 1951 to 1967 at the School of Veterinary Medi- cine, University of California, Davis (UCD); and 122 were diagnosed among beagles kept in the Radiobiology Laboratory colony (RLC), also at Davis, in a life-span study which began in 1950. In the ANR group about 18% of the dogs




with malignant neoplasms were available for autopsy in the first 3 years of the study.

The 122 RLC female beagles were divided into non-irradiated (control) and irradiated groups. The control group consisted of 48 beagles, of which 22 had mammary tumors. The x-irradiated (250 kvp; 30 ma) groups of dogs received fractionated or single exposures when 10 to 12 months of age. The dosage totalled either 100 R or 300 R. Group I (100 R) consisted of 135 beagles, of which 50 had mammary tumors. Group 11 (300 R) consisted of 139 beagles, of which 50 had mammary tumors. The RLC beagles were kept for life-span studies. Between 1 and 4 years of age approximately one-half of the dogs in each group were bred and whelped 2 litters. This provided information on mammary tumors with respect to whelping and the effect of whole-body x-irradiation. This colony differed from the other dogs used in this study in that mammary tumors were not treated; rather, the tumors were given every opportunity to become malignant and cause death.

In most cases only 1 mammary neoplasm per dog in theUCDand ANR groups was submitted for diagnosis. When multiple tumors were submitted all tumors from each dog were counted as the same case for statistical purposes. When a dog had a benign and a malignant tumor only the malignant tumor was counted. There was no case where 2 malignant neoplasms of different types existed in the same dog.

Tissues for histologic examination were fixed in 10% neutral buffered for- malin. All tissues were embedded in paraffin, sectioned at bu, and stained with hematoxylin and eosin. The stains used on selected tissues included Von Icossa’s, periodic acid-Schiff, Giemsa’s, Masson’s trichrome, and Gomori’s calcium phos- phate for alkaline phosphatase.

Results

Effects of Irradiation

In the RLC group of dogs it was clear that irradiation at different levels had no significant effect on increasing the incidence or frequency of different types of mammary tumors (Table I). In fact, there was a higher percentage of tumors in the non-irradiated control group (46%) than in the 2 irradiated groups (37% and 36% respectively).

Duration of Mammary Tumors

The data on duration of tumors as reported by the owners of dogs in the UCD and ANR groups were incomplete. However, in general the adenomas were observed by the owners for 1 to 2 months and carcinomas from a few weeks to several years, with the greatest number for 2 to 6 months. A frequent observation was the rapid



Tabl

e I. E

ffec

ts o

f ir

radi

atio

n on th

e fr

eque

ncy

of d

iffe

rent

typ

es o

f m

amm

ary

tum

ors

in t

he r

adio

biol

ogy

labo

rato

ry c

olon

y 0

No.

and

per

cent

age

of d

iffe

rent

typ

es o

f m

amm

ary

tum

ors

Gro

up

s T

otal

N

o.

affe

cted

/ T

otal

P

apil

lary

C

arci

nom

a B

enig

n hI

alig

nant

O

steo

- M

alig

nant

am

ount

of

No

. tes

ted

No

. of

aden

oma

mix

ed

mix

ed

sarc

oma

myo

epit

he-

irra

diat

ion

and

yo

tum

ors

liom

a

Con

trol

s 0

22/4

8 (4

6%)

22 (

100%

) 1

(5%

) 14

(63

%)

4 (1

8%)

2 (9

%)

1 (

5%)

0 G

rou

p I

1O

OR

50/1

35 (

37%

) 50

(10

0%)

4 (B

Yo)

31 (

62%

) 10

(20

%)

2 (4

%)

0 3

(67

0)

Gro

up

I1

300R

50

/139

(36

%)

50 (

100%

) 5

(10%

) 33

(66

%)

5 (1

0%)

5 (1

0%)

0 2

(4%

)

X2

= 1

.54:

d. f

. =

2:

0.5

0>

~>

0.2

5.




growth of the carcinoma just prior to removal. Mixed tumors had slower growth than carcinomas, varying from 1 month to 1 or more years with most having a duration of at least 6 months. The malignant mixed tumors were of shorter duration than the benign mixed tumors ; the myoepitheliomas grew fairly fast.

The duration of tumors was followed much more accurately in the RLC dogs where the onset of the tumor was recorded during an annual examination of the mammary glands*. There were 48 dogs that died of mammary carcinoma and 23 dogs that had mammary tumors of other types (Table 11). Complete necropsies were performed on all dogs. There were 46 other dogs that had mammary tumors, but they were not included because their main cause of death was due to some- thing other than the mammary tumor or because the onset of the tumor was not recorded. The carcinomas had a duration of 3 months to over 6 years (average 2 to 4 years). The other types of mammary neoplasms had a duration of from 1 to over 6 years (average 3 to 4 years).

7'ableZZ. Duration of mammary tumor in 71 dogs in radiobiology laboratory colony

Time in months or vears

Tumor type 3-6 mo. 1 yr.

6 mo.- 1-2 yr. 2-3 yr. 3-4 yr. 4-5 yr. 5-6 yr. 6-7 yr.

Aden o m a 1 I 1 Carcinoma 2 5 8 6 17 8 1 1

Mixed tumor,

Mixed tumor,

Ostcosarcoma 1 1

hl yoepithelioma,

benign 1 3 1 1 1

malignant 1 2 3 2 1

malignant 1 1

The mean ages of dogs in the ANR and UCD series were similar, 10.0 and 9.7 years, respectively (Table 111). Both of these were exceeded by the ages in the RLC series. The average age for malignant neoplasms

* The figures must be corrected as plus or minus 1 year because of yearly intcrvals between examinations.



Canine hlammary Tumors 297

InbleZZZ. hlcan ages o f dogs with mammary tumors by tumor typc and source of specimen

Mean ages (years)*

'Tumor types Animal Ncopl. Univ. Calif., Radiobiol. Lab. Regist. Davis Colony

All types 10.0 9.7 11.7 Adcnoma 9.1 9.9 11.5 Carcinoma 11.0 9.9 11.6 Benign rnixcd 9.3 9.3 12.9 Malignant rnixcd 11.0 10.1 11.9

- ~ M yoepithelioma 11.2

* hIcan ages were not calculated for catcgorics with fewer than 5 dogs.

was approximately 2 years more than that for benign neoplasms in the ANR and UCD groups but was 1 year less in the RLC group.

Breed

In the ANR series, poodles were represented in a greater proportion in the adenoma group than in other mammary groups (Table IV). The ANR carcinoma group contained the lowest proportion of poodles. The breed distribution among different types of carcinomas was without consistent pattern.

Comparing the ANR and UCD series, several large differences as to breed were observed. The poodles, dachshunds, and Chihuahuas comprised higher percentages of the ANR series than of the UCD series.

Sex

There were more intact females than neutered females in the ANR and UCD series (Table V). The ratios were approximately 3 :1 and 8 : 1, respectively. Among the ANR cases, 20 (2.5%) were males and among the UCD cases 9 (2.0%) were males.

There were proportionally more carcinomas and fewer benign mixed tumors in the neutered compared with the intact females in the IJCD and ANR groups. However, the RLC beagles which were all intact had a higher proportion of carcinomas and a corresponding Iowcr proportion of benign and malignant mixed tumors than the



Tabl

e 11'.

Per

cent

dis

trib

utio

n of

dog

s w

itih

mam

mar

y tu

mor

s by

bre

ed, t

umor

type

, and

sou

rce

of s

peci

men

Tum

or ty

De

Sar

com

a B

reed

T

otal

A

deno

ma

Car

cino

ma

Ben

ign

mix

ed

Mal

igna

nt

hlyo

- m

ixed

ep

ithel

ioim

a A

NR

' U

CD

' A

NR

U

CD

A

NR

U

CD

A

NR

U

CD

A

NR

U

CD

A

NR

U

CD

A

NR

U

CD

3 (n

4=78

2) (

n=36

2) (

n=33

) (n

=20

) (n

-265

) (n

=15

8) (

n=41

1) (

n=14

2) (

n=61

) (n

=38

) (n

=6)

(n=

4)

(n=

4) (

n =

0)

Poo

dle

12.8

6.

6 24

.2

5.0

6.4

6.4

17.0

8.

5 8.

2 0.

0 0.

0 25

.0

0.0 -

Coc

ker

span

iel

11.1

24

.8

6.1

25.0

12

.8

21.5

10

.5

26.1

11

.5

34.2

0.

0 25

.0

25.0

-

g G

erm

an

0

C

r 1

0

Z

shep

herd

3.

1 3.

3 3.

0 0.

0 4.

2 2.

5 2.

2 4.

2 3.

3 2.

6 0.

0 25

.0

25.0

-

Chi

huah

ua

4.1

1.7

9.1

5.0

3.0

0.6

4.1

2.1

4.9

2.6

16.7

0.

0 0.

0 -

Dac

hshu

nd

13.8

7.

7 3.

0 5.

0 13

.6

3.8

14.6

13

.4

16.4

5.

3 0.

0 0.

0 25

.0 -

Box

er

4.1

4.4

6.1

5.0

5.7

5.1

2.4

4.9

4.9

0.0

16.7

0.

0 25

.0 -

2

Fox

terr

ier

0.5

2.8

0.0

5.0

1.1

2.

5 0.

2 3.

5 0.

0 0.

0 0.

0 0.

0 0.

0 -

Bos

ton

terr

ier

1.7

2.8

0.0

10.0

2.3

1.

9 1.

5 2.

8 1.

6 2.

6 0.

0 0.

0 0.

0 -

Oth

er3

46.4

44

.2

48.5

35

.0

47.1

55

.1

45.5

33

.1

47.6

47

.4

66.6

25

.0

0 0 -

Bea

gle

2.4

1.7

0.0

5.0

3.8

0.6

2.0

1.4

1.6

5.3

0.0

0.0

0.0 -

K

1 A

nim

al N

eopl

asm

Reg

istr

y.

f U

nive

rsit

y of

Cal

ifor

nia,

Dav

is.

3 O

ne s

arco

ma

in U

CD

gro

up b

ut b

reed

of

the

do

g u

nkno

wn.

4

Th

e nu

mbe

r of

dog

s of

kno

wn

bree

d.

3 In

clud

es o

ther

bre

eds

and

dogs

ide

ntii

ied

as c

ross

bred

or

mix

ed.

by guest on May 10, 2013 vet.sagepub.com Downloaded from


Canine Mammary 'rumors 299

Table V. Percent distribution of dogs with mammary tumors by source, sex, and tumor type

Tumor type

Source and sex No. of Ade- dogs noma

Carci- noma

Benign Malig- mixed nant

mixcd

Myo- Sar- epithe- coma lioma

University of California, Davis

All sexes 441 5.7 Intact female 320 4.1 Neutered female 43 11.6 Male* 9 22.2

All sexes 803 4.3 Intact female 558 4.3 Neutered female 191 5.2 Male * * 20 5.0

Animal Neoplasm Registry

Radiobiology Laboratorv Colony

Intact female 122 8.2

44.2 45.0 48.8 44.5

33.5 29.9 44.5 45.0

63.1

39.0 10.0 38.7 10.9 32.6 7.0 33.3 0.0

52.9 7.7 57.3 7.2 39.8 8.9 40.0 10.0

15.6 7.4

0.9 0.2 1.3 0.0 0.0 0.0 0.0 0.0

0.7 0.5 1.1 0.2 0.0 1.6 0.0 0.0

4.1 1.6

* Includes 8 intact males and 1 neutered male. ** Includes 18 intact males and 2 neutered males.

averages for the other 2 series. Males were infrequent in both the UCD and ANR series and had no consistently greater frequency of any particular type of mammary tumor.

Functional Stages of Mammary Glands

The functional stages of the uninvolved, presumably normal mammary tissue in glands containing tumors were designated as follows : I. Resting stage - Mammary tissue with poor lobular development, presence of alveolar buds and ducts, but no alveoli. 11. Lobulo- alveolar stage - Mammary tissue with lobular formation, well-spaced alveoli lined with cuboidal epithelium, alveoli with or without secretion, similar to gland in 1 month of pregnancy. 111. Lactating stage - Enlarged lobules, alveoli lined by flattened epithelium and dilated by copious secretion, similar to gland after 8 weelis of pregnancy.

In a combined total of 516 dogs from the UCD, RLC, and ANR groups where the functional stages of the non-neoplastic mammary



300 ~ I O U L T O N , c t al.

tissue were recorded, 46 (8.9%) had mammary tissue in stage I, 53 (10.3%) - stage I or 11, 342 (66.2%) - stage 11, 60 (11.6%) - stage I1 or 111, and 15 (2.9?'0) - stage 111. There was no significant difference among the UCD, RLC, and ANR groups. When the functional stages were correlated with the different types of tumors, it was found that dogs with carcinomas had a wider range of functional stages than dogs with the other types of tumors. Approximately twice the number of dogs with carcinomas had mammary glands in the resting stage and thrice as many had a mixture of early and late lactating stages than dogs with benign mixed tumors.

Sites

The more caudally located mammary glands (abdominal and inguinal) were involved most commonly with the various tumors (Table VI). This was consistent among the UCD, ANR, and RLC groups and there was no difference among the different types of neoplasms.

Classification

The classification of the mammary tumors was based on the pre- dominant histologic features as well as on histogenesis (Table VII).

Approximately half of the total number of tumors in the study was malignant. The series from the RLC colony contained by far the highest proportion of malignant tumors, followed in order by the UCD series and the ANR series. The major contribution to the differences in the benign-malignant ratios of the series from different sources was the relative frequency of carcinomas and benign mixed mammary tumors in each group. There were more benign mixed tumors than carcinomas in the ANR series, while the carcinomas outnumbered the benign mixed tumors in both the UCD and RLC series.

Gross and Microscopic Pathology

Papillary Adenoma

Gross. The papillary adenomas were usually solitary lesions that measured up to 4 cm in greatest diameter and were round or ovoid.



Tabl

e VI. L

ocat

ion

as t

o m

amm

ary

glan

d of

528

* tu

mor

s ~

~~

hIam

mar

y gl

ands

6

Tu

mo

r ty

pe

No

. of

N

o. o

f A

xill

ary

Tho

raci

c C

entr

al

Abd

omin

al

Ingu

inal

5'

tu

mor

s do

gs

No.

";b

N

o.

"/b

No.

yo

No. yo

N

o.

yo

5;

3

Tot

als

528

407

54

10.3

68

12

.8

91

17.3

11

6 22

.0

199

37.8

9

Ade

nom

a 37

22

4

10.8

6

16.2

6

16.2

9

24.5

1

2

32.5

2

Car

cino

ma

233

195

25

10.7

22

9.

4 39

16

.7

58

25.0

89

38

.2

$ B

enig

n m

ixed

18

6 15

5 17

9.

1 31

16

.7

32

17.2

33

17

.7

73

39.3

hl

alig

nant

mix

ed

12

9

12.5

14

19

.5

16

22.0

25

35

.0

2 35

8

11.1

v)

* Ide

ntit

y of

mam

mar

y gl

and

invo

lved

was

kno

wn

in o

nly

528

of 1

366

dogs

in th

is s

tudy

.

by guest on May 10, 2013 vet.sagepub.com Downloaded from


302 ~ ~ O U L T ~ N , et al.

7ahle VZZ. Classification of 1366 canine mammary tumors by type and sourcc of spccimen

Source, number and percentage of tumors

’Tumor types Total UC, Davis Anim. Neo. Rad. Lab. Reg. Col.

No. yo No. yo No. % No. ”/o All types 1366 100.0 441 100.0 803 100.0 122 100.0 Adenoma 70 5.1 25 5.8 35 4.3 10 8.2 Fibrosarcoma 2 0.0 0 0.0 2 0.3 0 0.0 Carcinoma 541 39.7 195 44.0 269 33.5 77 63.0 Mixed, benign 616 45.1 172 39.0 425 52.9 19 15.6 Mixed, malignant 115 8.5 44 10.1 62 7.7 9 7.4 Myoepithelioma 15 1.1 4 0.9 6 0.8 5 4.1 Sarcoma 7 0.5 1 0.2 4 0.5 2 1.7

Usually they were embedded in the parenchyma and less often they were in the teat cistern. They were firm, sometimes soft, often cystic, lobulated in the solid areas, and gray, white, or tan. Most were well circumscribed.

Microscopic. The only pure adenomas in this series were the papillary adenomas or so-called “duct papillomas” which developed withm the lobules from the alveoli (and intralobular ducts) or in the interlobular ducts (Fig. 1). They formed within the lobule when the alveoli dilated and became separated from one another by thin stromal septa. When these membranes broke, the lobule was converted into a single cyst with intraluminal papillae. Papillary adenoma also developed when intraluminal papillae formed in dilated interlobular ducts.

These tumors were often multiple within the mammary gland. The epithelium covering the papillae was single or multi-layered ; the glandular lumens often contained acidophilic secretion.

Some of these tumors had proliferation of myoepithelial cells in the stroma of the papillae. These cells widened the papillae, forming large blunted masses that sometimes occupied the entire lumen. This type of tumor was classified as a benign mixed tumor if the myoepithelial cells were numerous or if cartilagenous metaplasia occurred.

ClassiJication and Histogenesis of Carcinoma

The mammary carcinomas were divided into lobular, papillary, solid, infiltrating, and squamous types (Table VIII). A diagram of the histogenesis of the carcinomas is shown in Fig. 2. Infiltrating carcino-



Canine Mammary Tumors 303

F&. I . Papillary adenoma with cystic spaces containing papillary ingrowths H&E, x 42.

Table VIII. Classification of 571 canine mammary Carcinomas by type and source of specimen

'Totals

No. :d, 541 100.0 56 10.4 91 16.8

116 21.4 239 44.2 39 7.2

Carcinoma types

All types Lobular Papillary Solid Infiltrating Sauamous

Sourccs of tumors

UC, Davis Anim. Neo. Rad. Lab.

No. No. yo No. '/" 195 100.0 269 100.0 77 100.0 27 13.8 24 8.9 5 6.5 30 15.4 54 20.1 7 9.1 34 17.5 61 22.7 21 27.3 89 45.6 114 42.3 36 46.7 15 7.7 16 6.0 8 10.4

Reg. Col.

ma was the most common, constituting over 40% of the carcinomas in each of the 3 groups of dogs. Solid carcinoma was the second most common, varying from approximately 17 to 27% in the different groups. It was unusually high in the RLC group of dogs. Papillary carcinoma, the third most common carcinoma, occurred most often in the ANR group, followed by the UCD and RLC groups. Lobular carcinoma was next in frequency followed by squamous carcinoma.



304 ~ I O U L T O N , et al.

P 0




Lobdar Carcinoma

Gross. About half of the lobular carcinomas measured less than 5 cm in greatest diameter, a few were over 10 cm in diameter. They were round, ovoid, or, less often, discoid. Usually they were soft, sometimes firm, and characteristically lobulated.

Microscopic. Lobular carcinoma (alveolar carcinoma, alveolar or lobular carcinoma in situ) arose from the alveoli and alveolar ducts within the mammary lobule (Fig. 3). Occasionally i t invaded the intralobular stroma. If invasion occurred outside of the lobule, the tumor was classified as infiltrating carcinoma.

Often it was difficult to distinguish between this form of carcinoma and hyperplastic change in the lobule, particularly when separate lobules became neoplastic at the same time. The following points were aids : When carcinoma developed the alveolar epithelial cells changed from a small, dark-staining type to a large, lighter-staining type. The latter cells were often stratified or had budlike growth. They sometimes sloughed into the lumens of the alveoli. In hyperplasia the epithelium was more regular, usually single layered, and often secretory.

Papilary Carcinoma

Gross. Most of the papillary carcinomas were less than 5 cm in greatest diameter and rarely over 10 cm in diameter. They were round, ovoid, or discoid. Approximately half were firm and half were soft. On cut section they were often lobulated and gray or white.

Microscopic. Papillary carcinoma developed de nouo or from malignant change in papillary adenoma. Usually it was multicentric with si- multaneous neoplastic change in separate, unrelated parts of the mammary gland. Papillary carcinoma arose de novo in 3 ways: It developed (1) when an alveolus or alveolar duct dilated and formed intraluminal papillae, (2) when multiple alveoli ddated and their thin, intervening stromal septa ruptured, converting the lobule into a cystic mass containing papillae; or (3) when interlobular ducts became dilated and papillomatous. It was estimated that about 18% of the papillary carcinomas developed from the mammary lobules and the rest developed from the interlobular ducts or from carcinomatous change in papillary adenoma.



306 M O U L T O N , et a1

The separation of papillary carcinoma from papillary adenoma was often difficult. Factors that aided in making this distinction were as follows. The carcinoma had piling up of the epithelial cells covering the papillae, frequent mitotic figures, and the presence of large cells with loss of polarity, having a cuboidal rather than columnar shape. Occasionally, in the carcinomas the epithelial cells detached and accu- mulated in the glandular lumens; seldom was there secretion in the glandular lumens.

Of the papillary carcinomas 46% had invaded the papillary stalks, interlobular stroma, capsule, or local lymphatics.

Solid Carcinoma

Gross. Most of the solid carcinomas (diffuse carcinoma, medullary carcinoma) were less than 5 cm in greatest diameter; a few were over 10 cm in diameter. They were usually round, ovoid, or discoid, firm or soft, lobulated, and white or gray.

Microscopic. Solid carcinoma developed from extensive intralobular invasion in lobular carcinoma and conversion of lobules into solid masses of cells with inapparent stroma, epithelial overgrowth and invasion in papillary carcinoma with the papillary projections converted into solidly cellular masses, or diffusely infiltrative carcinoma with cords of invading cells packed in so tightly they formed solid masses. Solid carcinoma was most common in the RLC dogs that had a longer time for neoplastic development than the UCD or ANR dogs.

Solid carcinoma was composed of solid masses of highly undifferentiated cells arranged in focal masses or diffuse sheets. Some had a faintly tubular pattern. It was easy to confuse solid carcinoma with undifferentiated myoepithelioma when both neoplasms were highly cellular and had minimal amounts of stroma.

In jha t ing Carcinoma

Glross. About half of the infiltrating carcinomas (carcinoma simplex, scirrhous or sclerosing carcinoma) were less than 5 cm in diameter, a third were 5 to 10 cm in diameter, and the rest were over 10 cm in diameter. They were round, ovoid, discoid, or irregular in shape, and poorly circumscribed. Occasionally they invaded into adjacent



Canine bfammary Tumors 307

mammary glands. They were hard, white, gray, or tan, and occasionally mottled brown or yellow. Some adhered to the overlying skin or to the underlying musculature.

Microscopic. Invasion was the outstanding feature of infiltrating carcinoma. This tumor arose from all other types of carcinomas but its exact origin, alveolar or ductal, could not always be determined. There was no clear separation of this carcinoma from solid carcinoma when there were broad masses of invading cells with scanty stroma.

Usually there was a total breakdown of lobular pattern in this neoplasm. The infiltrating cells were arranged as small tubules in 51 YO of the tumors (Fig. 4), solid ducts with or without necrotic centers (comedocarcinoma) in 25% (Fig. 5), thin cords of cells or cells infiltrating individually in 23% (Fig. 6), and as mucin-producing cells in less than 1 %. The invading tubules were irregular in size and shape, usually laclied secretion, and often contained detached cells. The cells of infiltrating carcinoma were cuboidal or irregular in shape and had loss of polarity.

An important feature of this carcinoma was extensive fibrous stroma in the areas of infiltrating cells.

Squamous Carciizoma

Gross. Squamous carcinomas were 5 to 9 cm in greatest diameter, irregular in shape, hard, lobulated, and gray or white with yellow mottling .

Microscopic. These neoplasms arose from the epithelium of the interlobular ducts or mammary cistern and usually appeared with solid cords, rarely tubules, of invading cells that had undergone squamous metaplasia. The formation of keratin “pearls” was common. There were usually large areas of suppuration and necrosis.

Benign Mixed Tumor

Gross. About 83% of the benign mixed tumors measured less than 5 cm in greatest diameter; many of these were less than 1 cm in diameter. About 10% measured 5 to 9 cm in diameter and 7% were 10 to 20 cm in diameter. Mixed tumors were round or ovoid and less often discoid. Mixed tumors were firm and often cartilagenous or



308



Canine hlammary 'Tumors 309

bony. Solid areas were lobulated and white or gray. Soft areas were reddish and spongy or consisted of cysts filled with mucinous fluid. Usually, mixed tumors were well circumscribed and encapsulated.

Microscopic. The mixed tumors appeared as adenomas with proliferation of fibrous stroma and myoepithelial cells. The myoepithelial cells often had metaplastic transformation into hyaline cartilage. Osteoid and osseous tissue formed by endochondral ossification of cartilage.

The adenomatous component of mixed tumors arose from the epithelium of alveoli and ducts. The epithelial cells were well differentiated and formed small tubules, often containing acidophilic secretion. Isolated tubules among proliferating myoepithelial cells or stroma mimiclied the invasiveness of carcinoma.

The proliferating fibrous stroma in mixed tumors occurred first in interlobular and intralobular areas, splitting apart lobular elements and isolating groups of alveoli. Highly cellular fibroblastic tissue was difficult to distinguish from proliferation of myoepithelial cells.

Proliferation of myoepithelial cells was a common feature of mixed tumors. Initially small intralobular foci of foamy cells appeared adjacent to alveoli (Fig. 7). Later, these cells proliferated throughout the lobule causing collapse of alveoli; often they broke out of the lobules into the interlobular stroma.

Cartilage developed by metaplasia of myoepithelial cells (Fig. 8). First it appeared as chondromucinous stroma in which myoepithelial cells were suspended and later as true hyaline cartilage. Osteoid that developed in these tumors usually formed in peripheral parts of the cartilagenous plates. It often became mineralized, indistinguishable from mature bone; in some tumors, there was bone marrow with active hematopoiesis.

Fig. 3. Origin of carcinoma from lobular acini. Some acini arc occluded by tumor

Fig. 4. Infiltrating carcinoma with infiltration of small, irregular tubules in a

Fzg. 5. Ductal formation in infiltrating carcinoma with ducts partly occluded by

1-28. 6. Carcinomatous cells infiltrating individually in fibrous stroma. H&E, x 155.

cells. H&E, x 100.

fibrous stroma. H&E, x 70.

ingrowth of tumor cells. H&E, x 100.




Fig. 7. Benign mixed tumor with nodular masses of proliferating myoepithelial cells. Observe the vacuolated, chondromucinous appearance of the myoepithelial cells and adenomatous glandular tissue. H&E, x 100.

Fig. 8. Proliferation of myoepithelial cells in benign mixed tumor with formation of chondromucinous stroma. H&E, x 67.

Fig. 9. Malignant myoepithelioma with bundles and nests of elongate cells. H&E, x 140.




Malignant Mixed Tumor

Gross. Malignant mixed tumors varied from 2 cm to 10 cm or more in diameter. They were often well circumscribed, firm, lobulated, and white or gray.

Microscopic. The malignant tissue in these neoplasms appeared as carcinoma in 65, myoepithelioma in 44, osteosarcoma in 1, a mixture of carcinoma and osteosarcoma in 2, and carcinoma and myoepithelioma in 3.

Metastasis in malignant mixed tumor only appeared as carcinoma; sarcoma and myoepithelioma were never found in metastatic sites although myoepithelial cells were sometimes observed in lymphatics in the primary sites. Two malignant mixed tumors had benign- appearing epithelial and myoepithelial components in both the mammary glands and regional lymph nodes. One of these had carcinomatous metastases in the lungs.

Mjoepithelioma

Gross. Most myoepitheliomas were less than 4 cm in diameter, round or ovoid, soft, ulcerated, and poorly circumscribed.

Microscopic. Only pure malignant myoepitheliomas were included in this group. When malignant myoepithelioma was found in mixed tumor, the tumor was classified as malignant mixed. Usually malignant myoepithelioma had whorls and bundles of cells and loss of lobular structure (Fig. 9). The cells had clear or vacuolated cytoplasm and round or elongated, “cigar shaped” nuclei. Vast areas of necrosis of tumor cells were common in malignant myoepithelioma. In some tumors the myoepithelial cells could be distinguished from fibroblasts* with Masson’s trichrome stain. The neoplastic myoepithelial cells stained red like normal myoepithelial cells or epithelial cells, whereas the fibrous stroma stained bluish-green. Some of the cells of myoepithelioma stained by Gomori’s alkaline phosphatase method reacted positively with brownish deposits in the cell cytoplasm.

* Editor’s note: The cytoplasm of fibroblasts stains red with Masson’s trichrome stain as does that of myoepithelial and epithelial cells.




Sarcoma

Gross. Pure osteosarcoma and chondrosarcoma were large, hard or gritty in cutting, and white or gray. These tumors were most common in the RLC group.

Microscopic. The osteosarcomas were composed of proliferating osteoblasts and osteoclasts with trabeculae of osteoid or mineralized bone. In chondrosarcoma there were masses of immature hyaline cartilage surrounded by undifferentiated chondroblasts.

Metastasis

The sites of metastases were usually not recorded for the UCD and ANR dogs from which biopsy specimens were received. The most common sites for metastasis of carcinoma were the inguinal or axillary lymph nodes. Metastases were found also in other lymph nodes, lungs, liver, spleen, skin, adrenal, intestine, heart, kidney, uterus, mesentery, pancreas, brain, skeletal muscle, thyroid, and urinary bladder.

In 1 dog, metastases from a mammary osteosarcoma were found in the lymph nodes, lungs, liver, and kidney; in a dog with malignant myoepithelioma, metastases were found in the lungs and liver. Metas- tatic carcinomatous cells were found in the lymph nodes and lungs of 4 dogs with malignant mixed tumors.

Discussion

As of January 1968, 66% of 322 deaths in the RLC dogs were attributable to neoplasms of all types and two-thirds of these neoplasms were of mammary origin. A summarization of the data on the tumors of all types revealed that the cause of death due to neoplasms was similar in the irradiated and control dogs, but neoplasms occurred at an earlier age in the irradiated than in the control dogs. Thus, the total incidence of tumors was the same but the age specific incidence differed in the control and irradiated dogs. This could be due to the shortening effect of irradiation on life-span.

Analysis of the data in the present study established that neither incidence nor type of mammary tumor could be correlated with irradiation.




In the UCD and ANR groups, there was an average period of 2 to 6 months between the time mammary tumors were first noticed and subsequently excised. These data were based on observations of the owners and are probably not very accurate. In contrast, in the RLC dogs which were allowed to live a full life-span, the average duration of tumor growth was 2 to 4 years. It was surprising that the canine species which has a relatively short life-span could have carcinomas for such a long time.

The greater mean age of RLC compared with UCD and ANR dogs with tumors can be explained on the basis of the ages of the RLC dogs being recorded at the end of a full life-span though the tumor might have first developed several years before. The ages of dogs in the other 2 groups were recorded at the time of removal of the tumor, usually less than 6 months after the tumor was first noticed by the owner.

The onset of mammary tumors in dogs compares well with the onset of mammary carcinomas in women. The risk of developing these tumors increases markedly at about 6 years of age in the dog and begins at around 40 years of age in women. One year of a dog’s life is equivalent to about 7 years of a woman’s by this measure499 60. A correction must be made for different breeds of dogs. For example, the giant breeds of dogs are “old dogs” at 5 to 8 years of age whereas the smaller breeds are only “middle-aged” at this period.

Fibroadenoma, one of the chief benign tumors in women and the benign mixed tumor, its closest equivalent in the bitch, begin at a younger age than carcinoma, the main malignant neoplasm in both species.

There was no significant difference as to breed in the incidence of mammary tumors. The differences as to breed between the UCD and ANR series (Table IV) correspond to shifts in the breed composing the population from which drawn between 1951 when the UCD series began and 1963 when the ANR series began. A comparison between RLC beagles and pet beagles could not be made because there is no information on incidence of tumors in pet beagles.

The data on the lower frequency of mammary tumors in bitches that were bred regularly and had many litters compared with bitches that were virgins or had only a few litters were difficult to explain. Perhaps the bitches in the second group had periods of incomplete hyperplasia or regression of mammary tissue, making the mammary gland more susceptible to neoplastic change.



314 M O U L T O N , e t al.

The relative percentages of bitches in the various mammary functional stages described in this study were as expected in a random sample of a normal population of dogs on the basis of the influence of the estrual cycle alone. Thus, no correlation could be made between the physiologic state of the mammary gland and the formation of neoplasms.

In this and other studies33 34, 40, 423 43, 60, it has been shown that both benign and malignant mammary tumors occur with increasing frequency from the most cephalad to the most caudal mammary glands. The 2 most caudal glands (abdominal and inguinal) had almost 60% of the mammary tumors in the present study. The reason for this is unknown although MULLICAN~* suggested that it might be associated with the greater activity in response to estrogen in the more caudal glands. Since these are the largest glands, they may be subject to a greater range of physiologic change and thus may become more susceptible to neoplasms.

In this study we were interested in multiple sites of involvement as well as multiple types of tumor, and we actually solicited the sub- mission of as many samples as possible. However, there was probably under-reporting of recurrences and metastases.

Another source of error was injected into the study when 1 type of neoplasm was counted per dog. Mammary glands of aged bitches contain anywhere from dozens to more than a hundred “lumps” that range in size from a few mm to 10 cm in diameter. There are signs of malignancy in the smallest as well as the largest of these lesions, and lesions from the same individual may encompass a wide range of morphologic types.

The general classification of mammary tumors is agreed upon by most investigatorslg, 20, 24, 371 47, 51,603 72. Even myoepithelioma is gain- ing acceptance as a classificational category199 59. However, the classification of carcinomas is far from satisfactory for it is based on too many criteria. It is based on the prominent tissue change (papillary carcinoma), cellular change (squamous carcinoma), histogenesis (lobular or alveolar-duct carcinoma), and infiltration or not (infiltrating or non-infiltrating carcinoma). It is also complicated because both infiltrating and non-infiltrating types of lobular, papillary, and alveolar-duct carcinomas occur.

An ideal classification of carcinomas would be based on the origin of the carcinoma (hstogenetic classification) and designation as to infiltration or not. Unfortunately, the origin of many invasive carci-




nomas cannot be determined. For example, the origin of a carcinoma cannot be determined when there is complete loss of lobular structure or invasion of single cells or thin cords of cells. In the past infiltrating carcinomas have been classified on the basis of stromal reac- tion (scirrhous or fibrosing carcinoma), tubular arrangement (adenocarcinoma), solid pattern (carcinoma simplex, medullary carcinoma), or necrosis in solid ducts (comedocarcinoma). Many were labeled “duct carcinomas” although their ductal origin could not be determined with certainty.

The development of solid carcinoma from other forms of carcinomas probably accounted for the higher incidence of this type of carcinoma in the RLC dogs where it had a longer time to develop this change.

We are opposed to the theorylp 42 that the cartilage and bone in mixed tumor arise from metaplasia of epithelial cells or that it develop solely from metaplasia of connective tissue59 32, 33, 41,453 62, 69, 73. It can arise at least in part from metaplasia of connective tissue but the bulk of the cartilage probably arise from metaplasia of myoepithelial

Proliferation and subsequent metaplasia of myoepithelial cells occurred coincidental with the degree of differentiation of epithelial cells. When the epithelium was well differentiated, as in benign mixed tumor, the myoepithelial cells were stimulated; when the epithelium was undifferentiated, as in carcinoma, the myoepithelial cells were unchanged and fibroplasia developed.

It was difficult to explain why 2 malignant mixed tumors appeared histologically benign in both the primary sites in the mammary gland and metastatic sites in the regional lymph nodes. Perhaps the carcinomatous element metastasized and stimulated the mixed tissue changes in the lymph nodes or perhaps both epithelial and connective tissue elements metastasized. This finding was disturbing for it indicated that some of the mixed tumors that were diagnosed as benign hsto- logically may have been potentially malignant. This suspicion was borne out further in consideration of the low incidence of benign mixed tumors and high incidence of malignant mixed tumors in the RLC group. This suggested that if the benign tumors were allowed sufficient time to grow they could change into malignant tumors.

A review of the literature and study of 1366 cases of canine mammary tumors revealed that additional research is needed, particularly on rates of incidence that include population-at-risk denominators,

cells7, 19, 30, 31, 39, 59.



316 M O U L T O N . et al.

susceptibility of breeds, effects of ovario-hysterectomy, endocrinic disorders, and the effects of continuous whelping compared with the infrequent whelping or the virginal state. Also, the possibility of preneoplastic lesions in the mammary gland must be studied. An at- tempt must be made to adopt a standard method of classifying these neoplasms, particularly the carcinomas. Additional information is needed on the development of cartilage and bone in the mixed tumors and the part played by myoepithelial cells in this process since there is still controversy on this subject. A detailed study by light and electron microscopy should be made of the steps in this change. A system is needed for more efficient follow-up of dogs that have had mammary tumors removed so that more accurate information may be obtained on the frequency and sites of metastases. It is also important to estab- lish more colonies of dogs, like the RIX group in the present study, to determine more clearly the duration of tumors and the frequency of change from benign to malignant tumors. The data are still incomplete on the effects of X-irradiation on the incidence of mammary tumors. However, there are indications that irradiation have no effect on the incidence of mammary tumors although the tumors occur at an earlier age in irradiated than in control dogs.

A retrospective study was conducted of 1,366 cases of canine mammary neoplasms derived from 3 different populations of dogs. The mean ages for occurrence of mammary tumors varied between populations studied from the ninth to eleventh years with malignant neoplasms tending to occur later than benign. Irradiation had no effect on incidence.

Poodles had the largest numbers of papillary adenomas and benign mixed tumors. Dachshunds, Chihuahuas, and cocker spaniels had a large proportion of all other types. Papillary adenomas arose from the ductile or alveolar epithelium and accounted for only 5.1% ofthe tumors. Benign mixed tumors comprised 45.1% and consisted of an adenomatous epithelial component and proliferative fibrous connective tissue or myoepithelium which frequently had undergone metaplasia to cartilage or bone. Malignant mixed tumors accounted for 8.5%, their malignant component being most frequently epithelial.

Carcinomas represented 39.7% of the tumors. More carcinomas were seen among neutered than intact females except in the closed beagle colony where carcinoma was the most frequent neoplasm in the exclusively intact female population. Among the carcinomas, an infiltrating type, usually comprised of ductile cells infiltrating an abundant fibrous stroma, was the most common. A solid type, comprised of masses of epithelial cells with scant or inapparent stroma, was next



Canine Mammary 'rumors 317

in frequency. Papillary, lobular, and squamous types of carcinomas occurred in descending order. Malignant myoepitheliomas comprised 1 .I% of the tumors ; fibrosarcomas, osteosarcomas, and chondrosarcomas were rare, accounting for less than 1%. Approximately 2% of the neoplasms were from males which had no predilection for a particular type of tumor.

Acknowledgements

This study was supported in part by General Research Support Grant 5457, National Institutes of Health, U.S. Public Health Service; Public Health Service Grants CA 05924 and CA 07730 from the National Cancer Institute; and Grant EP-6 from the American Cancer Society.

We wish to thank Dr. L. J. FAULKIN for helpful suggestions.

ReJ' erences

1. ALLEN, A.C. : So-called mixed tumors of the mammary gland of dog and man.

2. ANDERSEN, A.C.: Parameters of mammary gland tumors in aging beagles.

3. ANTOINE; LIEGEOIS and VERSTRAETE: Contribution a l'itude des tumeurs chez

4. APOSTOLEANO, E. : Tumeurs de la mammelle chez les carnivores domestiques.

5. AULER, H. and WERNICKE: Uber Tumoren des Hundes. Z. Krebsforsch. 35:

6, BECKMAN, C.H. : Sexual hormones in treatment of mammary tumors of aged

7. BIGGS, R.: The myoepithelium in certain tumours of the breast. J . Path. Bact.

8. BLOOM, F.: Pathology of the Dog and Cat, The Genitourinary System, with Clinical Considerations, p. 418-424 (American Veterinary Publications, Evan- ston, Illinois 1954).

9. BRACA, F.: Primitive tumours of the male mamma of the dog. Projlassi 6:

10. BRAEMER, C. : Die Mammatumoren bei der Hundin. Inaug. Diss., Humboldt- Univ., Berlin (1951).

11. BRODEY, R.S.; FIDLER, I.J. and HOWSON, A.E.: The relationship of estrous irregularity, pseudo-pregnancy, and pregnancy to the development of canine mammary neoplasms. J. amer. vet. med. Ass. 149: 1047-1049 (1966).

12. CATELLANI, G. : Sul comportamento della fosfatasi alcaline nelle displasie e nei tumori della cagna. A c t a med. vet. (Napoli) 2: 131-152 (1956).

13. COHRS, R.: Ober primare Multiplizitat von Geschwulsten bei Haustieren. 2. Krehsforsch. 24: 156-221 (1926).

Arch. Path. 29: 589-624 (1940).

J . amer. vet. med. Ass. 147: 1653-1654 (1965).

le chien. Bull. Acad. YOJ. Mid. Be&. 14: 301-319 (1934).

Rev. Path. conzp. 25: 1-7 (1925).

1-46 (1931).

bitches. Vet. Med. 40: 20-23 (1945).

59: 437-444 (1947).

254-256 (1933).




14. CORSY, F. and SURMONT, J.: Sur la prolifkration simultanke des deux assises myo-kpithtliale et skcrktoire dans les tumeurs mammaires de la chienne. C.R. Soc. Bid. 94: 84-87 (1926).

15. COTCHIN, E. : Neoplasms in small animals. Vet. Rec. 63: 67-72 (1951). 16. COTCHIN, E. : Further observations on neoplasms in dogs, with particular re-

ference to site of origin and malignancy. I. Cutaneous, female genital and ali- mentary systems. Brit. vet. ]. 110: 218-230 (1954).

17. COTCHIN, E.: Neoplasia in the dog. V e t . Rec. 66: 879-885 (1954). 18. COTCHIN, E. : Neoplasms of the Domesticated LMammals. Commonwealth

Agriculture Bureaux, Review Series No. 4. Farnham Royal, pp. 97 (1956). 19. COTCHIN, E. : Mammary neoplasms of the bitch.]. comp. Path. 68: 1-22 (1958). 20. DAHME, E. and WEISS, E. : Zur Systematik der Mammatumoren des Hundes.

Dfsch. tierarxtl. Wschr. 65: 458-461 (1958). 21. D A SILVA, R.A.; AMORIM, L. DE M. and CARDOSO, S.B.: Estudos sobre a

occorencii de tumoures mammarios na cadela. Veterinaria (S. Paulo) 1: 49-54 (1 947).

22. DE KOCK, G.: Pathological studies on neoplasms of dogs in South Africa. Onderstepoort]. vet. Res. 29: 35-54 (1952).

23. DE VITTA, J.: Mammary adenofibroma of the female dog. N. amer. Vet. 20: 53-55 (1939).

24. DIETZMANN, U.: Beitrag uber das Vorkommen von Geschwiilsten beim Hund. M h . vet. Med. 17: 8-12 (1962).

25. DOBBERSTEIN, J. and MATTHIAS, D. : Ober das Mammacarcinom bei der Hun- din. Arch. wiss. prakt. Tierheilk. 78: 18-31 (1942).

26. DORN, C.R.; TERBRUSCH, F.G. and HIBBARD, H.H.: Zoographic and demo- graphic analysis of dog and cat ownership in Alameda County, California, 1965. State of California, Department of Public Health, Berkeley, California,

27. DORN, C.R.; TAYLOR, D.O.N.; FRYE, F.L. and HIBBARD, H.H.: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. I. Metho- dology and description of cases.J. nat. Cancer Znst. 40: 295-305 (1968).

28. DORN, C.R.; TAYLOR, D.O.N.; SCHNEIDER, R.; HIBBARD, H.H. and KLAU- BER, M R . : Survey of animal neoplasms in Alameda and Contra Costa Counties, California. 11. Cancer morbidity in dogs and cats from Alameda County. ]. nut. Cancer Znst. 40: 307-318 (1968).

29. DOZZA, G. and COLUZZI, G.: Dosaggio biologic0 degli estrogeni urinari in cagne affette da tumori della mammella. Atti Soc. ital. Sci. vet. 17: 354-359 (1963).

30. ERICHSEN, S. : Connective tissue mucin-producing carcinoma of the canine mammary gland. Acta path. microbid. scand. 36: 481-489 (1955).

31. ERICHSEN, S. : A histochemical study of mixed tumours of the canine mammary gland. Actapath. microbial. scand. 36: 490-502 (1955).

32. EWING, J.: Neoplastic Diseases, 3rd ed. (Saunders, Philadelphia 1968). 33. FELDMAN, W.H. : Neoplasms of Domesticated Animals. (Saunders, Philadel-

34. FIDLER, I. J. and BRODEY, R.S. : A necropsy study of canine malignant mammary

35. FOREMAN, R.J.: Metastatic chondromata in dog. Vet. /. 69: 240-241 (1913).

pp. 1-37 (1967).

phia 1932).

neoplasms.]. amer. vet. med. Arr. 151: 710-715 (1967).




36. FROHNER : Vorkommen der Geschwiilste beim Hunde. Monatsh. prakt. Thierh. 6: 1, 79 and 111 (1895). Quoted by Feldman, 1932.

37. FRYE, F.L.; DORN, C.R.; TAYLOR, D.O.N. ; HIBBARD, H.H. and I<LAUBER, M.R. : Characteristics of canine mammary gland tumor cases. Anin/al Hospital

38. GARDNER, W.U. : Inhibition of mammary growth by large amounts ofestrogen. EndocrinoloD 28: 53-61 (1941).

39. HAMPERL, H. : Uber die hlyothelien (Myo-epithelialen Elemente) der Brust- driise. Virchows Arch. path. Anat . 305: 171-215 (1940).

40. HUGGINS, C. and MOULDER, P.V.: Studies on the mammary tumors of dogs. I. Lactation and the influence of ovariectomy and suprarenalectomy thereon. J . exp. Med. 80: 441-454 (1944).

41. HURLEY, J.V. and JABARA, A.G.: Properties of “cartilage” in canine mammary tumors. Arch. Path. 77: 343-347 (1964).

42. JABARA, A.G.: Canine mixed tumours. A w t r . vet. J . ?6: 212-221 (1960). 43. JABARA, A.G. : Canine mammary carcinomata. Ansf r . vet . ] . 36: 389-398 (1960). 44. JACKSON, C. : The incidence and pathology of tumours of domesticated animals

in South Africa. Onderstepoort J . vet. Sci. 6: 3-460 (1936). 45. JAEGER, A. : Zur Metaplasiefrage und den organoiden Entwicklungsvorgan-

gen der Tumorgenese, dargelegt an den Mammablastomcn dcs Hundes. Vircho2vs Arch. path. A n a t . 199: 95-130 (1910).

46. KLARENBEEK, A. and BUSSEMAKER, H. : Het voorkomen von tumoren bij den hond. 1’. Diergeneesk. 62: 1183-1185 (1935).

47. I<RONBERGER, H.: l<ritische Sichtung des dem Institute in den Jahren 1917- 1959 eingesandtcn Geschwulstrnaterials von Haussaugeticren. Mh. g e t . Med.

48. KROOK, L.: A statistical investigation of carcinoma in the dog. A c t a path.

49. LEBEAU, A , : L’age du chien et celui de I’homme. Essai de statistique sur la

50. MASON, n4.M. : Canine Mammary Tumors, A Review. MasonResearch Institute,

51, MISDORP, W. : Malignant mammary tumours in the dog and the cat compared

52. MISDORP, W. and DEN HERDER, B.A.: Bone metastasis in mammary cancer.

53. MOULTON, J.E. : Histological classification of canine mammary tumors: Study

54. MouLroN, J.E.: Tumors in Domestic Animals (Univ. of Calif. Press, Berkeley

55. MULLIGAN, R.h l . : hlultiple primary tumors in dogs. Cancer Res. 4: 505-509

56. MuLLIcAN, R.M.: Some statistical aspects of canine tumors. Arch. Path. 38:

57. hfULLIGAN, R.hI. : Some endocrinologic considerations of canine neoplastic

58. MULLIGAN, R.M.: Some effccts of chronic doses of stilbestcrol in female dogs.

3: 1-12 (1967).

16: 296-302 (1961).

microbial. scand. ?5: 407-422 (1954).

mortalit6 canine. Bdl. Acad. u i t . Fr. 26: 229-232 (1958).

Worchester, Mass., pp. 15 (1967).

with the same in the woman. Diss. Utrecht, pp. 184 (1964).

Brit. J . Cancer 20: 496-503 (1966).

of 107 cases. Cornell Vet. 44: 168-180 (1954).

1961).

(1 944).

115-120 (1944).

diseases. Arch. Path. 39: 162-171 (1945).

Exp. Med. Siirg. 5: 196-205 (1947).




59. MULLIGAN, R.M.: Neoplasms of the Dog (Williams and Wilkins, Baltimore 1949).

60. MULLIGAN, R.M. : Comparative pathology of human and canine cancer. A n n . N. Y. Acad. Sci. 108: 642-690 (1963).

61. MURRAY, J.A.: The zoological distribution of cancer. In: BASHFORD, E.F., ed. Third Scientific Report, Imperial Cancer Research Fund, London, pp. 41-60 (1908).

62. NIEBERLE, K. : Zur Kenntnis der sogenannten Mammamischgeschwiilste des Hundes. Z. Krebsjorsch. 39: 113-127 (1933).

63. PEYRON, A.: Dkveloppement des tumeurs de la glande mammaire chez la chienne. Rev. ve‘t. (Toulouse) 76: 764765 (1924).

64. POPPENSIEK, G.C. : Neoplasms Studied in Selected Veterinary Diagnostic La- boratories in the United States and Canada. New York State Veterinary Col- lege, Cornell University, Ithaca (1961).

65. RISER, W.H.: Surgical removal of the mammary gland of the bitch. ,/. amer. vet. med. Ass . 110: 86-90 (1947).

66. SANDERSLEBEN, J. : Beitrag zur Frage der Malignitat der Mammatumoren des Hundes. Mh. Tierheilk. I f : 191-198 (1958).

67. SASTRY, G.A. : Neoplasms of animals in India. An account of neoplasms col- lected in 12 years. Vet. Med. 54: 428-430 (1959).

68. SCHLOTTHAUER, C.F. : Neoplasms in the mammary gland in dogs, their pathology and surgical treatment.]. anzer. vet . med. Ass . 96: 632-640 (1940).

69. SCHMIDT, I.: Zur Frage der Entstehung der Mischgewachse, an Hand von zwei Fallen von Milchdrusenmischgeschwulsten des Hundes. Virchows Arch. path. Anat . 291: 491-506 (1933).

70. SCHNEIDER, R.; DORN, C.R. and TAYLOR, D.O.N.: Factors influencing canine mammary cancer development and postsurgical survival. J . nat. Cancer Znrt. 43: 1249-1261 (1969).

71. STICKER, A. : Uber den Krebs der Thiere. Insbesondere uber die Empfanglich- keit der verschiedenen Hausthierarten und iiber die Unterschiede des Thier- und Menschenkrebses. Arch. klin. Chir. 65: 616-696; 1023-1087 (1902).

72. UBERREITER, 0. : Neubildungen bei Tieren. Wien. tierurxtl. Mschr. 47: 805-832 (1960).

73. WILLIS, R.A.: Pathology of Tumours, pp. 212-213, 230 (Mosby, St. Louis 1948).

74. World Health Organization Report: International Study Group for the Com- parative Study of Mammary Tumors. Washington Meeting, pp. 1-9 (1968).

Author’s address: Dr. J. E. MourroN, Dept. of Pathology, University of California, Uovir, California (USA).



Documents

Pathol Vet 1970 Moulton 289 320