Original Article
DOI: 10.1111/j.1476-5829.2009.00184.x
Canine mammary gland tumours; a histological continuum from benign to malignant; clinical and histopathological evidence* K. U. Sorenmo1,2,3 , V. M. Kristiansen2 , M. A. Cofone2,4 , F. S. Shofer1 , A.-M. Breen2 , M. Langeland2 , C. M. Mongil5 , A. M. Grondahl2 , J. Teige2 and M. H. Goldschmidt1,3 1 School
of Veterinary Medicine of the University of Pennsylvania, Philadelphia, PA, USA School of Veterinary Science, Oslo, Norway 3 Mari Lowe Center for Comparative Oncology, University of Pennsylvania, PA, USA 4 Veterinary Specialty Center of Delaware, Wilmington, DE, USA 5 Centro de Especialistas Veterinarios de Puerto Rico, Puerto Rico 2 Norwegian
Abstract
Keywords breast cancer, comparative oncology, dog, malignant transformation, tumour
This study describes the clinical and histopathological findings in dogs with mammary gland tumours, and compares the histopathological and clinical evidence consistent with progression from benign to malignant to human breast cancer epidemiology. Clinical and histopathological data on 90 female dogs with 236 tumours was included. Dogs with malignant tumours were significantly older than dogs with benign tumours (9.5 versus 8.5 years), P = 0.009. Malignant tumours were significantly larger than benign tumours (4.7 versus 2.1 cm), P = 0.0002. Sixty-six percent had more than one tumour, and evidence of histological progression was noted with increasing tumour size. Dogs with malignant tumours were significantly more likely to develop new primary tumours than dogs with benign tumours, P = 0.015. These findings suggest that canine mammary tumours progress from benign to malignant; malignant tumours may be the end stage of a histological continuum with clinical and histopathological similarities to human breast carcinogenesis.
Introduction Spontaneous tumours in companion animals represent a valuable and underutilized resource in cancer research. Companion dogs develop tumours Correspondence address: K. U. Sorenmo Department of Clinical studies Veterinary Hospital of the University of Pennsylvania 3900 Delancey Street Philadelphia PA 19104 e-mail: karins@vet.upenn.edu
spontaneously, are relatively out-bred, immunologically competent and share their living environment with humans. The complex interaction between the
*This study was performed at the Norwegian School of Veterinary Sciences, Ullevalsveien 72 Postboks 8146 Dep, 0033 Oslo, Norway and Centro de Especialistas Veterinarios de Puerto Rico, RR16 #3250 San Juan, Puerto Rico 00926.
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tumour and the host microenvironment associated with tumour development and tumour progression may therefore be effectively captured in these natural models and as such provide a unique insight into cancer biology. The range of cancers diagnosed in dogs varies as much as those in humans and share many similar features in terms of histopathology, biological behaviour, hormone dependence, risk factors and genetic alterations as their human counterparts.1 Furthermore, the therapeutic challenges and the obstacles to a cure are also similar; and metastasis and drug resistance are major cause of treatment failure in both dogs and humans. Thus, c 2009 Blackwell Publishing Ltd
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spontaneous tumours in dogs not only provide opportunities to study cancer biology, but also the effectiveness of novel therapies.1 Results from such research may have direct applications for human cancer patients. Comparative oncology research can strengthen the relevance of these spontaneous tumour models by identifying further similarities between canine and human cancers, both at the clinical, histological, biological and molecular level. Canine mammary gland tumours are already recognized as models for human breast cancer. Previous studies have identified many similarities between canine mammary tumours and breast cancer in women in terms of epidemiology, biology, dietary risk factors, clinical behaviour as well as hormonal association.2 Mammary tumours are the most common types of tumours in intact female dogs and comprise more than 40% of all tumours in this particular patient population.3 Breast cancer is also the most common cancer in women and one of the leading causes of cancer death.4,5 The development of mammary tumours in dogs is dependent on exposure to ovarian hormones and the tumour risk can be significantly reduced by performing ovariohysterectomy (OHE) at an early age.6 The risk for developing breast cancer in women is also associated with the cumulative exposure to bio-available estrogens, suggesting that similar hormone driven mechanisms might be linked with breast carcinogenesis in both species.7,8 Current theory suggests that most human breast cancers originate from specific pre-malignant benign lesions within the breast; numerous studies have found an increased risk for later breast cancer in women with previous biopsies such as atypical ductal hyperplasia and carcinoma-in-situ.9 – 13 Furthermore, the risk for a new primary breast cancer is also higher in women with a previous malignant breast biopsy; the risk is highest in the ipsi-lateral breast, but the risk is also increased in the contra-lateral breast suggesting that these pre-malignant lesions are both precursors as well as predictors of later breast cancer development.9,10,14 – 16 In fact, these epidemiological and histopathological studies suggest that invasive breast cancer might be the end results of a histological continuum of progressive changes from benign to malignant resulting from
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hormonally driven field carcinogenesis of breast tissue. Dogs have five pairs of mammary glands and the incidence of multiple tumours has been reported to be as high as 60%.17,18 Despite the relatively common occurrence of synchronous multiple mammary tumours, little is known about how or if these tumours relate to each other. Most reports state that they are independent primary tumours with different histopathological features, and it is recommended that all tumours should be biopsied to determine malignancy.18,19 It is therefore assumed that benign and malignant tumours are separate entities and one is not a precursor of the other. However, a recent publication reported an increased risk of developing new malignant primary tumours in other mammary glands in dogs with a previous diagnosis of a mammary carcinoma compared to dogs with previously diagnosed benign tumours, and yet another study reported on a high incidence of concurrent carcinoma-in-situ in dogs with carcinomas.20,21 These two reports provide additional evidence that there might be further similarities in breast cancer/mammary tumour carcinogenesis and epidemiology between dogs and humans; and suggest that canine mammary carcinoma may be a result of hormonal field carcinogenesis effect on mammary tissues and that synchronous and metachronous tumours are indeed associated with each other. Dogs with mammary tumours might provide an excellent opportunity to study the various stages of mammary tumour development and thus improve our understanding of why and how some tumours undergo malignant transformation. The purpose of this study is to describe the clinical and histopathological findings in dogs with mammary gland tumours. We wanted to specifically examine the association between clinical and histopathological characteristics, including the histopathological association between tumours in dogs with multiple tumours, and find out whether there is evidence of progression and how the histopathological findings correspond with outcome, specifically the risk for developing new tumours.
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Methods Clinical and histopathological data from sexually intact privately owned female dogs with mammary tumours participating in a prospective randomized trial to determine the efficacy of surgical ovarian hormonal ablation, OHE were used in this study. All dogs were enrolled and treated at the Norwegian School of Veterinary Sciences and Centro de Especialistas Veterinarios in Puerto Rico. This study was approved by the Institutional Animal Care and Use Committee (IACUC) and owners of the dogs consented to have their dog participate in the study. A complete history including information regarding, age, breed, reproductive history, use of progestins, previous malignant tumours, duration of tumour growth and other concurrent medical problems was obtained for all dogs. All dogs underwent complete staging prior to surgical resection of their mammary tumours. The staging tests included routine bloodwork (complete blood count, serum chemistry profile), urinalysis, fine needle aspirates of palpable draining lymph nodes and three-view thoracic radiographs). Dogs with previous malignant mammary tumours, distant metastasis or other serious medical problems were excluded from participating in this study. The mammary glands were examined carefully and all tumours were recorded and measured. The surgical resection was performed according to standard practice, with an aim to remove all of the tumour/tumours with complete margins. The type of surgery, that is lumpectomy, simple mastectomy or regional mastectomy depended on the tumour size, location and the number of tumours present in the individual dog. If necessary, the surgeries were staged in two phases in order to prevent excessive tissue tension and wound dehiscence in dogs with multiple large tumours. All of the tumours were submitted for histopathological examination. Two independent pathologists (MHG and JT) performed the evaluations blinded to each other and all of the clinical information about the case. The tumours were classified according to type of tissue present (epithelial, myoepithelial and/or connective tissue) and whether they were malignant or benign. The malignant simple epithelial tumours were grouped together as carcinomas for the purpose of this study
and included papillary and tubular adenocarcinomas, solid carcinomas and anaplastic carcinomas. A complete histopathological description was provided for each tumour and included information regarding the degree of tumour differentiation, presence of cellular atypia, carcinoma–in-situ, vascular/lymphatic invasion and surgical margins. The diagnosis also included histopathological assessment of the entire section including dysplastic changes and was not limited to only the neoplastic changes. Dogs with large tumours had multiple sections evaluated. The original biopsy reports (used in the main study to evaluate the effect of OHE on remission and survival) were used for this study; the pathologist did not review the biopsy report with the specific purpose of identifying evidence of histopathological progression.
Follow-up Dogs that were found to have at least one malignant epithelial tumour were scheduled to return for regular examinations every 4 months to monitor for local tumour recurrence, new tumour development and metastasis. Dogs with benign tumours were followed through phone calls with theirs owners and re-examined as needed. Complete necropsies were requested in all dogs with malignant tumours when they died.
Variables In order to determine whether there was an association between clinical characteristics and malignancy, the following variables were examined: age, number of tumours, duration of tumour growth and tumour size. Dogs that had one or more malignant tumours were classified as malignant and dogs that had only benign tumours were classified as benign. The mean size of all benign tumours within the benign group and the mean size of all malignant tumours in the other dogs were compared. To further examine the relationship between size and malignancy, the tumours were grouped by size (cms) (<1, 1–<2, 2–<3, 3–<5, ≥5) and classified as benign or malignant. In dogs with multiple tumours, the histopathological lesions were examined to determine whether there
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were any similarities or other evidence suggesting an association between them. Information regarding outcome, specifically the development of new primary tumours, was extracted from follow-up visits and through phone calls with owners. If available, histopathological results from these new primary tumours were also recorded. In order to analyse whether a diagnosis of a benign tumour, ca-in-situ or carcinoma conferred an increased risk for new tumours developing later, the following comparisons were made: Dogs with benign tumours were compared to dogs with cain-situ, and dogs with benign tumours (including ca-in-situ) were compared to dogs with at least one malignant tumour.
Statistical methods Continuous data was expressed as means ± standard deviation (SD) and categorical data as frequencies and percentages. To assess differences between malignant and benign tumour groups, Student’s t-test was used for continuous variables (e.g. age, tumour size) and a chi-square or Fisher’s exact test (2 × 2 tables) was used for categorical or binominal variables. Significance was set at P < 0.05. All analyses were performed using SAS statistical software.
Results
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Table 1. Tumour size versus malignancy Benign Tumour size <1 cm 1 to <2 2 to <3 3 to <5 >5 Total
Malignant
n
%
n
%
96 50 27 16 10 199
48.2 25.1 13.7 8.0 5.0 100%
1 4 6 13 13 37
2.7 10.8 16.2 35.1 35.1 100%
Total n 97 54 33 29 23 236
P < 0.0001, likelihood ratio chi-square.
a relatively indolent, stagnant tumour for several weeks to months that suddenly changed behaviour and grew quickly. There was a strong association between tumour size and malignancy; only one of a total of 37 malignant tumours (3%) was smaller than 1 cm, while 96 out of the 199 benign tumours (48%) were less than 1 cm. The risk of being malignant increased gradually as the tumour diameter increased; 70% (26/37) of the malignant tumours were larger than 3 cm (Table 1). There was no statistically significant difference between dogs with malignant and benign tumours in terms of exposure to exogenous hormones (progestins and estrogens) or parity, P = 0.5 and 0.36, respectively. However, only 13 dogs had a previous history of hormone treatment and 15 dogs had one or more litters.
Histopathology
Clinical data Information on 90 dogs with a total of 236 tumours was available for analysis. Clinical parameters: Thirty-one (34.5%) of the 90 dogs had at least one malignant tumour and 60 of the 90 dogs (66.7%) had more than one tumour. Dogs with malignant tumours were significantly older than dogs with only benign tumours, with a mean age of 9.5 years versus 8.5 years, P = 0.009. Malignant tumours were also significantly larger than benign tumours, with a median diameter of 4.7 cm versus 2.1 cm, P = 0.0002. There was no significant difference between the number of tumours or duration of tumour growth between dogs with malignant and benign tumours. The mean duration of tumour growth was between 22 and 35 weeks, and some of the owners would explain that their dog had
The majority of dogs with malignant tumours had tumours of epithelial origin: carcinomas (n = 35), complex carcinomas (n = 2). Three of these dogs had other concurrent malignant tumours of non-epithelial origin or malignant mixed tumours (osteosarcoma, carcinosarcoma, malignant myoepthelioma). Complex adenoma (n = 64), adenoma (n = 44), lobular hyperplasia (n = 37) and benign mixed tumours (n = 27) were the most common primary diagnosis in the benign category. Other diagnoses in the benign/dysplastic/pre-malignant category included adenoma with atypia, duct ectasia, ca-in-situ, epitheliosis, and lactational activity. Many of these benign histologies were often found in conjunction with malignant tumours. Histopathological heterogeneity (the presence of more than one
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distinct histopathological diagnosis, i.e. carcinoma, complex adenoma, lobular hyperplasia or other combinations)22 was noted within the same sections, between different sections from the same tumour, as well as between the individual tumours from the same dogs. Twenty-one of the 31 dogs with a malignant tumour had other concurrent histopathological lesions within the same section or tumour, and 22 had more than one tumour. In the 22 dogs with multiple synchronous tumours, the malignant tumour was the largest in 21 out of the 22 cases. Many of the dogs had evidence of progressive histopathological changes that corresponded with increasing tumour size, smaller lesions were consistently diagnosed as benign lobular hyperplasia, adenomas or complex adenomas. As the tumour became larger, areas of atypia or ca-in-situ were noted. Twenty-one of the dogs with malignant tumours had concurrent benign lesions within the same tumour, but of particular interest were four cases where the pathologist noted that the malignant tumour was arising within areas of a benign lesion, such as a carcinoma arising from a complex adenoma or a mixed tumour. Three of these cases had a carcinoma (simple type) arising from a complex adenoma and the fourth case had a carcinoma arising in a mixed tumour. Six dogs in the benign/pre-malignant group had ca-in situ lesions, five of which were arising in or immediately adjacent to a complex adenoma. In addition to this direct evidence of malignant tumours arising from within benign tumours, others had carcinomas, adenomas or complex adenomas on the same slide or immediate adjacent sections, see illustrations 1â&#x20AC;&#x201C;4. Figure 1 illustrates one of the cases where the carcinoma was noted to arise from within a complex adenoma. Figures 2 and 3 show examples of tumour heterogeneity (benign and malignant) in adjacent sections from the same tumours. Figure 4A,B captures a more complete picture of a stepwise progression from the benign/dysplastic epitheliosis via ca-in-situ to a carcinoma.
Risk for new tumour development We had adequate follow-up information on 81 of the dogs. Dogs with (carcinomas) had a significantly increased risk of developing new primary tumours
later: 15 (48.6%) of the 31 dogs with malignant tumours while only 11 (22 %) of the 50 with benign tumours (including ca-in-situ) developed new primary tumours, P = 0.015. Further subgroup comparisons found no significant difference in risk for later tumour development between dogs with benign tumours and dogs with ca-in-situ: Eight (18.2%) of the 44 dogs with benign tumours developed new tumours while three (50%) of the six dogs with ca-in-situ developed new tumours, P = 0.09. Histopathological examination was not available on many of these new tumours, but one of the three dogs that developed a new primary tumour after an initial ca-in-situ diagnosis was confirmed to have an anaplastic mammary carcinoma with widespread systemic metastasis within 1 year of the initial tumour. Four of seven dogs with a previous malignant tumour that were biopsied were confirmed to be malignant (carcinomas) in other glands within the first year. As a comparison, three of six dogs with an initial benign tumour that were biopsied had malignant new primary tumours. However, the majority of the new primary tumours were not biopsied as the owner chose not to pursue further treatment for their dogs.
Discussion The results from this study provide additional insight into canine mammary tumour development. The strong association between tumour size and malignancy, the low incidence of small malignant tumours and the evidence of histological progression with increasing tumour size in dogs with multiple tumours, suggest that rather than developing de novo as separate entities, malignant tumours develop from pre-existing lesions from within benign tumours. The clinical history provided by some owners regarding indolent tumours being present for a long time before suddenly undergoing a growth spurt further supports this theory. It is plausible that this sudden change in growth corresponds to malignant transformation and a change in tumour histopathology. The difference in size between malignant and benign tumours may in part be due to a higher growth rate in malignant versus benign tumours, but the higher
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Figure 1. Tumour heterogenecity within same section (A) Carcinoma arising in a complex adenoma (H&E Ă&#x2014; 20)
(B) Carcinoma arising in a complex adenoma (H&E Ă&#x2014; 60).
growth rate alone cannot explain the low number of small malignant tumours. It also raises an obvious question; where, if not from small malignant tumours, do the large malignant tumours come from? A reasonable explanation is that they may arise from within small benign tumours. The theory that malignant tumours develop from areas within pre-existing benign lesions is further supported by the fact that the malignant tumour was the largest tumour in all but one dog in the 22 dogs with multiple synchronous tumours. These dogs have already had sufficient exposure to develop one malignancy, but despite this fact, the smallest tumours were consistently benign. These findings
support the hypothesis that malignant transformation occurs via a prolonged clinical process through several specific histological steps. Moreover, the identification of cases in which it was noted that carcinomas and carcinomas-in-situ were arising within complex adenomas, and cases with concurrent carcinomas and carcinomas-in-situ within the same tumour provide direct and compelling evidence for a gradual transformation from benign to malignant tumours. The majority of the dogs in this study had only benign tumours, these dogs were significantly younger, and the tumours were significantly smaller than dogs with at least one malignant tumour.
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Figure 2. Tumour heterogeneity; adjacent sections same tumour (A) Complex adenoma (left) and carcinoma (right)
(H&E Ă&#x2014; 20) (B) Carcinoma (right) (H&E Ă&#x2014; 60).
As a comparison to human breast cancer, the majority of breast lesions detected by palpation or mammography are benign, only 1 of 10 such lesions is malignant. Similar to what we found in the dogs, younger women are more likely to have benign tumours and the risk for malignancy increases with age.23 The type of tumours also differ somewhat; complex adenomas were the most common benign tumours in the dogs whereas, fibroadenomas are more common in women, especially in younger patients.23 However, in both species carcinomas (simple type) are the most common malignant tumours.24 Our results are consistent with these findings. It is difficult to make
a comparison to human breast cancer regarding tumour size and malignancy as there is limited data available to examine the association between size and malignancy in human breast cancer. Many benign tumours are not biopsied if determined to be benign according to mammography. Furthermore, screening mammography has lead to a relative increase in early diagnosis, that is small breast cancers in women. There was no difference in the duration of tumour growth or how many tumours these dogs had between dogs with benign and malignant tumours. However, it is possible that some of these benign tumours might have progressed and
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Figure 3. Tumour heterogeneity; adjacent sections same tumour (A) Papillary ductal adenoma with focal sclerosis
(H&E Ă&#x2014; 20) (B) Carcinoma in tissue adjacent to papillary ductal adenoma (H&E Ă&#x2014; 20).
become malignant if opportunity (i.e. time) had been provided. Equally important; not all small benign tumours did progress or change; many of them remained stagnant in terms of growth while others did not acquire malignant features despite continuing to grow and becoming quite large. The answers to why some benign tumours transform and become malignant and why others do not might be found in molecular differences in these apparently histopathological similar adenomas and complex adenomas. It is also interesting to note that the complex adenomas were the most common benign tumour type, but relatively few complex carcinomas (n = 2) were diagnosed. Carcinomas (simple) were most common malignant tumour
type in this study. One possible explanation may be that complex adenomas are low risk tumours and do not transform to become malignant. An alternative explanation may be that only the epithelial component of these complex adenomas undergo transformation and become carcinomas. The latter may be supported by the fact that in three of the four cases described previously the carcinoma was arising from a complex adenoma, and that in five of the six cases with ca-in-situ, the ca-in-situ was arising in or adjacent to a complex adenoma. Sixty-six percent of the dogs in this study had more than one tumour. This is slightly higher than reported in previous studies, but this is likely because all of the dogs enrolled in this study were
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Figure 4. Tumour heterogeneity; different sections from same tumour (A) Epitheliosis and carcinoma-in-situ (H&E Ă&#x2014; 20)
(B) Intraductal carcinoma arising in adjacent sections (H&E Ă&#x2014; 60).
sexually intact dogs and their mammary glands have been under prolonged hormonal stimulation. The data used in this study was from dogs enrolled in a prospective randomized trial evaluating the efficacy of OHE in canine mammary carcinomas. The data collection, treatment and follow-up examination were systematic, consistent and organized. Therefore, the results offer a unique opportunity to evaluate the clinical and histopathological changes in multiple tumours from the same dogs from a more comprehensive perspective and not as individual events occurring over time. The clinical data and corresponding histopathological characteristics in dogs with multiple tumours in various phases of transformation may in fact tell a
more general story, not only breast cancer, of how benign tumours change over time and gradually transform, and bear many similarities to what has been described in humans with colon cancer where malignant transformation from benign adenomas or polyps to colon cancer occur via stepwise specific mutations.25,26 Many of the dogs developed new primary tumours during the follow-up period. Unfortunately, most owners elected not to pursue further treatment (surgery) despite recommendations to do so. As expected, the risk for developing new primary tumours was significantly higher in dogs with a previous diagnosis of a mammary carcinoma. It is possible that the incidence of new primary tumours
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in dogs with previous benign tumours is somewhat underestimated in this study since these dogs were not monitored by a veterinarian at regular intervals. However, we believe that this is not likely to significantly affect the results since these owners found relatively small tumours on their dogs in the first place and brought their dogs in for participation in the study. This experience most likely would have heightened their awareness of canine mammary tumours. It is also interesting to note that one of the three dogs with a ca-in-situ developed a high-grade mammary carcinoma within a year after the first surgery. These findings fit well into the field carcinogenesis model; the entire mammary tissues have been under the same prolonged hormonal exposure. Several different tumours may develop over time or be present in various stages of transformation; some may progress to malignancy and others may not. This further underscores the similarities in risk factors, biology and epidemiology between canine mammary tumours and human breast cancer: A woman with a previous breast biopsy is at increased risk of developing later breast cancer. This risk increased according to the result from the biopsy. The risk is highest in women with a previous malignancy, but is also increased in women with benign or pre-malignant lesions. Women with proliferative lesions without atypia have a relative risk of 1.5–2.0 of developing breast cancer compared to the general population; women with proliferative lesions with atypia (atypical ductal hyperplasias or atypical lobular hyperplasia) have a relative risk of 4–5, and women with ca-in-situ have an increased relative risk of developing invasive breast cancer of 8–10 higher than the general population over the next 10–15 years.9,13,14,23 This study provides clinical and histopathological evidence suggesting that spontaneous canine mammary tumours progress from benign to malignant. Canine mammary tumours provide a powerful spontaneous research model that lends itself readily to close clinical monitoring and easy access to repeated biopsy and tissue collection for molecular analysis; and as such, an invaluable resource to identify genetic events associated with malignant transformation secondary to hormone-driven field
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carcinogenesis. These studies may provide additional insight into mammary carcinogenesis, elucidate crucial initial events in malignant transformation and potentially identify targets for therapy that might be beneficial for both humans and dogs.
Acknowledgements This research was supported in part by a grant from Morris Animal Foundation (D04CA-107), Forskningsfondet Kreft hos hund (Translation: The research fund: Cancer in the dog), Oslo Norway, and the Department of Companion Animal Clinical Sciences, Norwegian School of Veterinary Sciences. No salary support for any of the co-authors was provided from these sources; the funding was used to cover clinical expenses and diagnostics for the dogs included in this study.
Conflict of interests The authors of this manuscript declare that we have no competing interests financial or non-financial that might have influenced our interpretation or presentation of the data presented in this manuscript.
References 1. Paolini M and Khanna C. Translation of new cancer treatments from pet dogs to humans. Nature Reviews Cancer 2008; 8: 147–155. 2. Sorenmo KU. Canine mammary gland tumors. In: The Veterinary Clinics of North America; Small Animal Practice; Update in Medical Oncology, B Kitchel, ed., Philadelphia, WB Saunders Co, 2003; 573–596. 3. Dorn CR, Taylor DO, Schneider R, Hibbard HH and Klauber MK. Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County. Journal of the National Cancer Institute 1968; 40: 307–318. 4. Jemal A, Siegel R, Ward E, Hao Y, Murray T and Thun MJ. Cancer statistics 2008. CA A Cancer Journal for Clinicians 2008; 58: 71–96. 5. Glass A, Lacey JV, Carreon D and Hoover R. Breast cancer incidence, 1980–2006: Combined roles of menopausal hormone therapy, screening mammography and estrogen receptor status. Journal of the National Cancer Institute 2007; 99: 1152–1161.
c 2009 Blackwell Publishing Ltd, Veterinary and Comparative Oncology, 7, 3, 162–172
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K. U. Sorenmo et al.
6. Schneider R, Dorn CR and Taylor DON. Factors influencing canine mammary cancer development and postsurgical survival. Journal of the National Cancer Institute 1969; 43: 1249–1261. 7. Bernstein L and Ross RK. Endogenous hormones and breast cancer risk. Epidemiologic Reviews 1993; 15: 48–65. 8. Yager JD and Davidson NE. Estrogen carcinogenesis in breast cancer. New England Journal of Medicine 2006; 354: 270–282. 9. Arpino G, Laucirica R and Elledge RM. Premalignant and in situ breast disease: biology and clinical implications. Annals of Internal Medicine 2005; 143: 446–457. 10. Hartman L, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, Vierkant RA, Maloney SD, Pankrantz S, Hillman DW, Suman VJ, Johnson Jo, Blake C, Tlsty T, Vachon CM, Melton LJ and Visscher DW. Benign breast disease and the risk of breast cancer. New England Journal of Medicine 2005; 353: 229–237. 11. Alpers CE and Wellings SR. The prevalence of carcinoma in situ in normal and cancer-associated breasts. Human Pathology 1985; 16: 796–807. 12. Bratthauer GL and Tavassoli FA. Assessment of lesions coexisting with various grades of ductal intraepithelial neoplasia of the breast. Virchows Archiv 2004; 444: 340–344. 13. London SJ, Connolly JL, Schnitt SJ and Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. Journal of the American Medical Association 1992; 267: 941–944. 14. Bernstein JL, Thompson WD, Risch N and Holford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. American Journal of Epidemiology 1992; 136: 925–936. 15. Hartman M, Czene K, Reilly M, Adolfson J, Bergh J, Adami HO, Dickman PW and Hall P. Incidence and prognosis of synchronous and metachronous bilateral breast cancer. Journal of Clinical Oncology 2007; 25: 4210–4216. 16. Allred DC, Mohsin SK and Fuqua SAW. Histologic and biological evolution of human premalignant
17.
18.
19.
20.
21.
22.
23.
24.
25. 26.
breast disease. Endocrine-Related Cancer 2001; 8: 47–61. Benjamin SA, Lee AC and Saunders WJ. Classification and behavior of canine mammary epithelial neoplasms based on life-span observations in beagles. Veterinary Pathology 1999; 36: 423–436. Fowler EH, Wilson GP and Koester A. Biologic behavior of canine mammary neoplasms based on a histogenic classification. Veterinary Pathology 1974; 11: 212–229. Misdorp W, Else RW, Hellmen E, Lipscomb TP: Histological classification of mammary tumors of the dog and cat. In: WHO International Histological Classification of Tumors of Domestic Animals,. Second Series, vol VII, Washington DC, Armed Forces Institute of Pathology, American Registry of Pathology, 2001. Stratmann N, Failing K, Richter A and Wehrend A. Mammary tumor recurrence in bitches after regional mastectomy. Veterinary Surgery 2008; 37: 82–86. Antuofermo E, Miller M, Pirino S, Xie J, Badve S and Mohammed SI. Spontaneous mammary intraepithelial lesions in dogs-a model of breast cancer. Cancer Epidemiology, Biomarkers & Prevention 2007; 16: 2247–2257. Cheng J, Qiu S, Raju U, Wolman SR and Worsham MJ. Benign breast disease heterogenecity: association with histopathology, age and ethnicity. Breast Cancer Research and Treatment 2008; 111: 289–296. Miltenburg DM and Speights AO. Benign breast disease. Obstetrics and Gynecology Clinics of North America 2008; 35: 285–300. Schenider R. Comparison of age, sex, and incidence rates in human and canine breast cancer. Cancer 1970; 26: 419–426. Fearon ER and Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759–767. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL. Genetic alterations during colorectal tumor development. New England Journal of Medicine 1988; 319: 525–532.
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