Page 39 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

18 PART I The Biology and Pathogenesis of Cancer

26% for dogs spayed after their second estrus. 237,238 Mammary controls for comparison to specifically investigate the effects that
tumors primarily affect late middle-aged (9 to 11 years) female spaying and age of spay have on the risk of feline mammary car-
cinoma development. Overley et al attempted to address these
intact dogs, and an increased incidence begins at approximately 6
VetBooks.ir years of age. 239 Despite the studies describing the protective effect issues in a retrospective study that compared a population of 308
cats with biopsy-proven mammary carcinoma diagnosed between
of spaying on mammary tumor development, the highest level of
evidence manuscript in veterinary medicine found only weak evi- 2000 and 2001 and a control population of 400 female cats not
dence of an association because of potential bias in almost all stud- diagnosed with mammary tumors but from the same biopsy ser-
ies screened. 240 A systematic review retrieved more than 11,000 vice population as the affected cats. Cats from the two groups
references, with only 13 studies published in peer-reviewed Eng- were frequency matched by age and year of diagnosis. 258 The study
lish language journals addressing the authors’ research question. reported a 91% reduction in risk for those spayed before 6 months
According to the Scottish Intercollegiate Guidelines Network of age and an 86% reduction in risk for those spayed before 1 year
(SIGN) level of evidence system, 9 of the 13 studies were judged of age, compared with intact cats. Although the study was retro-
to be at high risk of bias. The remaining four studies had mixed spective in nature and relied on questionnaire data from a survey
results, with some bias noted in all studies. The authors concluded with a 58% response rate, the manuscript is the first published
that some evidence suggested that neutering female dogs before report attempting to age match controls and evaluate age at time
2.5 years of age resulted in a considerable reduction in the risk of spay as a risk factor for mammary tumor development in cats.
of malignant mammary tumors, with further reduction possible Although further epidemiologic evaluation and prospective assess-
if neutering occurred before the first estrus. 240 Randomized con- ment are needed to confirm these findings, the reported results
trolled clinical trials published after this systematic review have provide some justification for recommending ovariohysterectomy
shown a protective effect. In dogs spayed at the time of mammary before 1 year of age in cats.
tumor excision, significantly fewer dogs subsequently developed
nonmalignant tumors than if they were not spayed at the same Lymphoma
time (hazard ratio 0.47). 241 The same group then looked at dogs
with malignant tumors and found a subset of dogs, those with The National Cancer Institute’s Surveillance, Epidemiology and
intermediate-grade and estrogen receptor–positive tumors, ben- End Results (SEER) data indicate that non–Hodgkin lymphoma
efited from ovariohysterectomy. 242 is approximately 50% more common among men than women. 259
Sexual steroid hormones likely have their primary effect on tar- Although a similar male predisposition is reported for canine lym-
get cells during the very early stages of mammary carcinogenesis in phoma, the underlying role of sex in lymphoma etiology remains
dogs; thus the protective effect of spaying is lost with time. 243–249 elusive. The author and others undertook a population-based
In addition to the influence of ovarian hormones on breast cancer study using the VMDB to determine the relationship between
development, the use of medroxyprogesterone acetate products sex and the development of canine lymphoma. 260 The VMDB
(progestin and estrogen combination) to prevent estrus or to treat included nearly 15,000 lymphoma cases in a population of more
pseudopregnancy has been linked to an increased incidence of than 1.2 million dogs over a span of 20 years. Intact female dogs
mammary tumor development in dogs. 250–252 were about half as likely to develop lymphoma compared with
Progestin-induced growth hormone (GH) excess in dogs origi- spayed females and with males, whether neutered or intact. 260 In
nates in the mammary gland. Within the mammary gland the addition, two breed-specific studies have evaluated gonad status
gene encoding GH may act in an autocrine/paracrine fashion, and lymphoma development. 261,262 Both studies concluded that
effecting cyclic epithelial changes and, perhaps, carcinogenesis. spaying increases the risk of lymphoma in golden retrievers 261 and
Research to determine the mechanism of progestin-induced mam- Vizslas. 262 A retrospective, single-institution medical record search
mary GH expression in dogs has led to the cloning and cellu- involving more than 90,000 dogs evaluated at the University of
lar localization of the canine progesterone receptor (PR). 253 The California–Davis (UCD), assessed odds ratios (OR) and neuter
investigators concluded that within the same mammary gland cell, status in multiple disease processes and neoplasms. 263 In this study
the activated PR may transactivate GH expression and function as spayed female dogs had more than double the risk (OR 2.25) of
a prerequisite transcription factor; however, this regulation may developing lymphoma compared with intact female dogs. 263 Male
be lost during malignant transformation. Mammary GH expres- castrated dogs also were at an increased risk of lymphoma diagno-
sion also has been reported in people, suggesting that evaluation sis compared with intact males. Further examination of the role
of links between this hormone and mammary carcinogenesis may of estrogen and neuter status in the development or prevention of
have implications for both species. 254,255 canine lymphoma is warranted.

Feline Mammary Cancer Osteosarcoma

Both estrogen and progesterone are thought to play important Although historically reported to be a disease more common in
roles in feline mammary carcinogenesis, although the underlying male dogs, a review of all dogs with OSA presenting to Colorado
mechanisms are less clear than for dogs. Prior studies have shown State University over 27 years found an equal male-to-female rela-
that intact female cats and cats exposed regularly to progestin are at tionship (see Chapter 25). A case-control study using the VMDB
an increased risk for mammary cancer development. The literature that evaluated gonad status and the development of OSA found a
also suggests that, as is the case in dogs, ovariectomy may be pro- twofold excess risk of OSA development among neutered dogs. 264
tective against mammary tumor development in cats. 194,256–258 In Data collected through questionnaires from owners of 683 rott-
one study, cats ovariectomized at 6 months of age had an approxi- weiler dogs from North America showed that the age of spay or
mate sevenfold reduction in risk of mammary tumor development neuter had a significant influence on bone sarcoma incidence. 265
compared with intact cats. 194 What has been lacking in the veteri- Both male and female dogs that underwent gonadectomy before
nary literature is an epidemiologic study of cats with age-matched 12 months of age were significantly more likely to develop a bone