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Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer
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Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer Marta Vascellari a,∗ , Katia Capello a , Antonio Carminato a , Claudia Zanardello a , Elisa Baioni b , Franco Mutinelli a a b
Istituto Zooprofilattico Sperimentale delle Venezie, Viale dell’università 10, 35020 Legnaro, PD, Italy Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle d’Aosta, Via Bologna, Torino, Italy
a r t i c l e
i n f o
Article history: Received 14 January 2015 Received in revised form 10 February 2016 Accepted 27 February 2016 Keywords: Dog Incidence Mammary tumors Population Risk factors
a b s t r a c t Although mammary gland tumors (MT) are the most-common type of tumor in intact female dogs, there is little information about their incidence in dog population. Data on MT in female dogs was retrieved from the Animal Tumor registry of dogs and cats of Venice and Vicenza provinces during 2005–2013 and was analyzed to visualize crude incidence rates by breed and across age categories. Overall, 2744 mammary tumors were reported accounting for 54% of all tumors in female dogs. The annual incidence rate (IR) was 250 cases per 100,000 dogs. The most frequent malignant tumors were complex carcinomas, consisting of both epithelial and myoepithelial tissues (IR = 71.89), and simple carcinomas (IR = 62.59). The MT incidence rate increased through the study period; particularly in the last 4 years, and malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Seventy-four percent of tumors were diagnosed in intact females, and the mean age at diagnosis was significantly higher for spayed dogs than for intact ones. MT were less frequent in dogs younger than 6 years and increased up to approximately 60% for ages between 8 and 13 years. The purebred dogs had a higher probability to have a malignant neoplasm than mixed-breed dogs, particularly in dogs younger than 7 years, and the Samoyed, Dobermann, Schnauzer and Yorkshire Terrier breeds were more inclined to develop malignant MT. The incidence of MT in dogs is increasing, and IRs are comparable to that in women. The epidemiological similarities between dogs and women support the validity of canine MT as a model for human breast cancer. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Dogs develop mammary gland tumors (MT) spontaneously, and some epidemiologic, clinical, and prognostic features are similar to human breast cancer (Owen, 1979; Misdorp, 2002; Vail and MacEwen, 2000; Mohammed et al., 2011). Despite the fact that MT are the most-common type of tumor in intact female dogs (Sleeckx et al., 2011), there is little information about their incidence in the dog population. Most of the information is based on data obtained from hospitals in which the population is only represented by cases referred to veterinary clinics, or biopsied and necropsied dogs (hospital-based registry). The scarcity of population-based canine registries is partly due to expense and difficulties in acquiring such
∗ Corresponding author. E-mail address: [email protected] (M. Vascellari).
data. Among commonly cited studies, Schneider (1970) reported an incidence of 145 per 100,000 dogs-year at risk amongst female dogs in California, USA. Some European studies showed an incidence rate of approximately 200 per 100,000 dogs-year (Dobson et al., 2002; Merlo et al., 2008; Vascellari et al., 2009). In general, more than 40% of tumors in female dogs are MT (Merlo et al., 2008; Vascellari et al., 2009; Dorn et al., 1968), and approximately 30–50% of canine MT are malignant (Dorn et al., 1968; Sorenmo et al., 2000). Many factors are known to influence the incidence of MT, such as breed, age, and spayed status. Results from different studies showed that the incidence rates of MT in purebred dogs are significantly higher than in mixed-breed (Merlo et al., 2008) and depending on the study, different breeds seem to have an increased risk of developing MT (Jitpean et al., 2012; Moe, 2001; Borge et al., 2011). As in humans, advanced age increases the risk of MT development in dogs, with a median age at diagnosis of approximately 8–10 years (Sleeckx et al., 2011). Furthermore, development of canine MT is hormone
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Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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dependent. Schneider et al. (1969) reported that ovariohysterectomy before the first, second, or third estrus cycle significantly reduces the relative risk of developing MT, while ovariohysterectomy later in life had no significant effect. Breast cancer is also one of the most common cancers in women living in Western countries (Youlden et al., 2012). Excluding skin cancers, breast cancer is the most common malignancy and the second leading cause of cancer death among women in the United States (Desantis et al., 2011). In 2002, the estimated agestandardized rate of breast cancer was equal to 40.4 new cases per 100,000 people worldwide (Parkin et al., 2005), and it increased to 42.3/100,000 in 2008 (Ferlay et al., 2010). After adjusting the number of new cases for population size and age, it emerged that incidence rates were almost 2.5 times higher in the more developed countries than in less developed ones (71.7/100,000 and 29.3/100,000, respectively) (Ferlay et al., 2010). A range of factors relating to lifestyle in more developed countries, such as having fewer children, giving birth at an older age and being less likely to breastfeed, may influence the incidence rate. Higher levels of obesity combined with lower levels of physical activity, increased alcohol consumption, and use of oral contraceptives and hormone replacement therapies, may also affect incidence (Youlden et al., 2012). Globally, 89% of breast cancers are diagnosed from the age of 40 onwards (Ferlay et al., 2010; Youlden et al., 2012). The main objective of this study was to describe the incidence of MT in female dogs living in the Venice and Vicenza provinces during 2005–2013 and to measure the incidence by breed and across age categories. The descriptive epidemiological data obtained have been compared with those obtained by the human cancer registries in the same area and globally.
while the recapture sample was obtained by a telephone survey of households of the Veneto Region (Capello et al., 2015). The canine population estimated in 2011, was 137.006 (95% CI 127.603–149.302), and it has been considered stable through the study period. The lower and upper limits of the 95% confidence interval of the population estimate were used as the denominator to provide the intervals of the IRs, later called “range”. The trend of IRs during the study period was evaluated after having split the observation period into 4 periods of 24 months each. The chi-squared test was used to compare the proportion of benign and malignant tumors and the proportion of complex and simple carcinomas during the study period. The Student’s t-test was used to assess differences in the mean age between dogs with malignant and benign tumors and between neutered and entire subjects. The Satterthwaite approximation was used to allow for variance heterogeneity. A logistic regression analysis was used to evaluate the association of spayed status, age, breed (pure and mixed-breed), and their interaction on the occurrence of malignant and benign tumors. The same statistical method was applied to malignant tumors and, particularly, to compare complex versus simple carcinoma (other types of malignant neoplasms were not considered in the analysis, given the low number of cases). For both models, the p-values obtained using type 3 analysis were used to evaluate the significance of the main effects. The odds ratios (OR) with 95% confidence intervals (95%CI) were used to summarize the results. To assess the distribution of cases among breeds, standardized morbidity ratios (SMRs) with 95% confidence intervals were calculated using the Canine Demographic Registry of the Veneto region as the reference population for the distribution of breeds in the general dog population. The SMR for a specific breed was obtained using o /C the formula: SMRb = nb /N where ob and nb are the number of cases
2. Material and methods
and the number of dogs for a specific breed, respectively, while C and N are the total number of cases in the ATR and the number of dogs in the reference population, respectively.
b
In April 2005 the Animal Tumor Registry (ATR) of Vicenza and Venice provinces of Veneto region (northern Italy) was established (Vascellari et al., 2009). This incidence registry, is based on an active surveillance program and includes both malignant and benign neoplasia. A network of collaboration with the veterinary clinics in Veneto region was established, inviting to submit any suspected neoplasm from dogs and cats living in the Vicenza and Venice provinces. The histopathology lab of the IZSVe, provides free cytological and histopathological evaluation to practitioners in the area of the registry. A standardized case-report form, specifically designed for the collection of canine and feline tumor cases, was made available to all veterinarians (Vascellari et al., 2009). MTs were classified according to the World Health Organization International histological classification of tumors of domestic animals (Misdorp et al., 1999), in order of malignancy in the following types: non infiltrating (in situ) carcinoma, complex carcinoma, simple carcinoma (tubulopapillary, solid, anaplastic), special types of carcinoma (spindle cell carcinoma, squamous cell carcinoma, mucinous carcinoma, lipid-rich carcinoma), sarcoma (fibrosarcoma, osteosarcoma), and carcinosarcoma. Benign tumors were classified into simple and complex adenoma, basaloid adenoma, fibroadenoma, benign mixed tumor, and duct papilloma. 2.1. Statistical analysis Crude and specific incidence rates (IRs) were calculated by dividing the number of cases by the estimate of the canine population of the registry catchment area, multiplied by the number of years. The estimate of the canine population was obtained by applying the Lincoln-Petersen version of the capture-recapture method (Seber, 1982): the capture sample was represented by the official Canine Demographic Registry established in Veneto region,
3. Results Overall 2744 MT were reported in 2359 dogs, accounting for 33% of all tumors in the whole population, and 54% in females. The annual incidence rate was 250 cases per 100,000 dogs, ranging from 229.74 to 268.80 per 100,000 dogs, given the confidence interval of the population estimate. Malignant tumors (1636, 60%, IR = 149.26 range: 136.97–160.26) were more frequent than benign neoplasms (1108, 40%, IR = 101.09 range: 92.77–108.54). The most frequent malignant tumors were complex carcinomas consisting of both epithelial and myoepithelial tissues (788, IR = 71.89, range: 65.97–77.19), and simple carcinoma (686, IR = 62.59, range: 57.43–67.20). Other tumors were special types of carcinoma (61, IR = 5.57, range: 5.11–5.98), carcinosarcoma (24, IR = 2.19, range: 2.01–2.35) and in situ carcinoma (17, IR = 1.55, range: 1.42–1.67). Fifty-eight tumors of mesenchymal origin (fibrosarcoma/osteosarcoma/other sarcomas) were collected (IR = 5.29, range: 4.86–5.68). Among benign tumors the most frequent were complex adenoma (485, IR = 44.25, range: 40.61–47.51), simple adenoma (320, IR = 29.20, range: 26.79–1.35) and mixed benign tumors, which are a combination of epithelial and mesenchymal tissues (251, IR = 22.90, 95%CI: 21.01–24.59). The MT incidence rate increased through the study period (Fig. 1), ranging from 178.82 (range: 164.10–192.00) to 313.12 (range: 287.34–336.20). A significant association between the classification of benign and malignant tumors and the 4 investigated periods was observed (pvalue < 0.001, Table 1), highlighting different trends between the two groups of tumors. At the end of the study period, malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Focusing on the most frequent types of malignant
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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Table 1 Number (n) and percentage (%) of benign and malignant tumors during the study period, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Type of neoplasm
Mammary tumors Benign Malignant Complex carcinoma Simple carcinoma Other malignant
April 2005–March 2007
April 2007–March 2009
April 2009–March 2011
April 2011–March 2013
Total
n
%
n
%
n
%
n
%
n
%
490 182 308 134 140 34
37.1 62.9 43.5 45.5 11.0
594 299 295 130 126 39
50.3 49.7 44.1 42.7 13.2
802 366 436 206 193 37
45.6 54.4 47.2 44.3 8.5
858 261 597 318 227 52
30.4 69.6 53.3 38.0 8.7
2744 1108 1636 788 686 162
40.4 59.6 48.1 41.9 10.0
Fig. 1. Trend of the incidence rates through the study period in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy); the error bars shows the intervals of the incidence rates, calculated using the lower and upper limits of the 95% confidence intervals of the population estimate.
MT, complex and simple carcinomas, a significant difference in the distribution of cases during the study period was noted (p-value 0.032), which principally resulted from the increase of complex carcinoma cases in the last two years. Spayed status, breed and age of tumor cases are shown in Table 2, while Table 3 reports the results of logistic regression analyses. Six hundred and ninety four (26%) tumor cases were detected in spayed subjects. The mean age at diagnosis was significantly higher
(p-value < 0.001) for spayed dogs (10.09 years, sd 2.57) than for intact females (9.20 years, sd 2.63). No significant differences in the proportion of malignant tumors were observed between spayed (60%) and intact dogs (58%). However, complex carcinoma occurred in a smaller proportion of the spayed dogs (43%) compared with simple carcinoma (57%). The opposite trend was seen in intact females (p = 0.007), providing an OR of 0.62 (95%IC: 0.44–0.88).
Table 2 Number (n) and percentage (%) of mammary tumors according to the spayed status, breed and age groups, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Mammary tumors Benign
Total Spayed status Entire Neutered NA Breed Pure breed Mixed breed NA Age (years) 0–3 4–5 6–7 8–9 10–11 12–13 14+ NA
Types of malignant neoplasms Malignant
Simple carcinoma
Complex carcinoma
Other types of carcinoma
n
%
n
%
n
%
n
%
n
%
1108
40.4
1636
59.6
686
41.9
788
48.2
162
9.9
828 268 12
41.1 38.6 34.3
1187 426 23
58.9 61.4 65.7
465 212 9
39.2 49.8 39.1
622 156 10
52.4 36.6 43.5
100 58 4
8.4 13.6 17.4
666 440 2
39.1 42.7 22.2
1038 591 7
60.9 57.3 77.8
436 244 6
42.0 41.3 85.7
506 281 1
48.7 47.5 14.3
96 66 0
9.2 11.2 0.0
28 76 199 322 273 145 42 23
60.9 62.3 48.4 43.4 37.9 33.7 30.9 16.8
18 46 212 420 447 285 94 114
39.1 37.7 51.6 56.6 62.1 66.3 69.1 83.2
8 22 70 157 179 144 49 57
44.4 47.8 33.0 37.4 40.0 50.5 52.1 50.0
8 22 132 227 220 100 32 47
44.4 47.8 62.3 54.0 49.2 35.1 34.0 41.2
2 2 10 36 48 41 13 10
11.1 4.3 4.7 8.6 10.7 14.4 13.8 8.8
NA: not available.
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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Table 3 Chi-square values and p-values for the significance of the spayed status, breed, age groups and their interactions, obtained by logistic regression (LR) analyses in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Effect
Breed Age groups Spayed status Breed × Spayed status Age classes × Spayed status Breed × Age groups
LR for malignant vs benign neoplasms
LR for complex vs simple carcinoma
Chi-Square
Pr > ChiSq
Chi-Square
Pr > ChiSq
7.89 46.17 1.37 0.65 5.05 13.55
0.005 <0.0001 0.2411 0.4218 0.4099 0.0188
1.72 22.15 7.29 0.46 4.93 8.25
0.1892 0.0005 0.0069 0.4987 0.4246 0.143
Fig. 2. Percentages of mammary tumors vs. other tumors in female dogs among different age groups, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy).
Fig. 3. Trend of incidence rates according to the age of diagnosis in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy); the error bars shows the intervals of the incidence rates, calculated using the lower and upper limits of the 95% confidence intervals of the population estimate.
The frequency of MT had a significant association with age groups (p < 0.001), and MT were less frequent in the first two age groups ( < 6 years) and increased up to approximately 60% for ages between 8 and 13 years (Fig. 2). In particular, a statistically significant increase (p < 0.001) in malignant tumors among age groups was noted, ranging from 39% to 69% in the youngest and oldest age group, respectively. The mean age at diagnosis was significantly higher (p < 0.001) for malignant tumors (9.74 years, sd 2.60) than for benign neoplasms (8.95 years, sd 2.66). Differences in the age at diagnosis between the two groups of tumors were noticeable in the age-specific incidence rates (Fig. 3). Moreover, the complex
carcinoma cases were diagnosed at younger ages (p < 0.001, 9.34 years, sd 2.44) than simple carcinoma cases (10.04 years, sd 2.71); in particular, dogs younger than 11 years were approximately 2 times more likely to develop a complex carcinoma (OR = 1.99, 95%CI: 1.45–2.75) than older dogs. Overall 1704 (62%) tumor cases were reported in purebred dogs with an IR of 282.67 (range: 259.39–303.50), and 1031 (38%) cases were reported in mixed-breed dogs with an IR of 209.03 (range: 259.39–303.50). A significant interaction between breed and age regarding the development of malignant versus benign tumors was observed (p-value 0.016), as reported in Table 4. The purebred dogs
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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M. Vascellari et al. / Preventive Veterinary Medicine xxx (2016) xxx–xxx Table 4 Proportion and Odds Ratio (OR) with the 95% confidence interval (95%CI) of malignant mammary tumors in pure breed dogs when compared to mixed breeds stratified by age class in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Age classes (years)
0–5 6–7 8–9 10–11 12–13 14+
% of malignant tumors Pure breed
Mixed breed
44.74 57.79 57.45 64.02 65.53 72.22
23.53 36.97 53.33 59.09 67.42 68.00
OR
95% CI
2.63 2.34 1.18 1.23 0.92 1.22
1.25–5.54 1.53–3.63 0.86–1.62 0.90–1.68 0.61–1.37 0.53–2.48
were approximately 2 times more likely than mixed-breed dogs to have a malignant neoplasm in both the age groups of 0–5 years (OR: 2.63, 95%CI: 1.25–5.54) and 6–7 years (OR: 2.34, 95%CI: 1.53–3.63). For the oldest age groups (>7 years), no differences between pure and mixed breed were found. In Fig. 4, the SMRs on malignant tumors by breed are reported. The Samoyed dogs were approximately twice as likely to develop malignant MT than the overall population, and were followed by Doberman, Schnauzer and Yorkshire Terrier with SMRs between 2 and 1.5. Conversely, the English Setter, Golden Retriever and Labrador Retriever had SMRs of 0.50, 0.36 and 0.36, respectively, indicating that the probability to develop a malignant MT for these breeds is lower than the population average. 4. Discussion The aim of this study was to provide descriptive epidemiological data on MT in female dogs living in Venice and Vicenza provinces, keeping in consideration incidence trends and individual risk factors. In fact, even though MT are one of the most frequent tumors in dogs, few population-based epidemiological studies are available (Dorn et al., 1968; Moe, 2001; Merlo et al., 2008; Vascellari et al., 2009; Brønden et al., 2010). The proportion of MT among other types of tumor was 33% in the whole population, and 54% in females. MT have the second highest incidence in the animal tumor registry of Vicenza and Venice provinces (IR 250 cases per 100,000 dogs ranging from 229.74 to 268.80). Malignant MT showed an IR of 149 new cases per 100,000 dogs/year, showing an increasing trend, particularly in the last two years. Since the registered cases were provided by veterinary practitioners on a voluntary basis, the estimated incidence could has been underestimated. The completeness of submissions in the catchment area was sought maximized by a capillary and continuous information of the veterinarians as well as providing the histopathological investigation free of charge. Other factors that might influence the results from the registry are the likelihood of dogs being brought to a veterinarian and willingness of the owner to pursue (and pay for) a diagnostic work-up for their dog. Unfortunately, these factors are hard to be estimated. Factors that may have led to the increase of MT incidence rates are the stabilization of the registry in the study area, leading to an increasing trend of sample submission, as well as the improvement of owners and veterinary care. However, it is worth noting that the increase of IRs is primarily associated with malignant tumors, while the IRs of benign neoplasms seems to decrease. Giving that no changes occurred in the diagnostic criteria during the study period (classification system, pathologists) other factors should be considered to explain this trend. The influence of environmental contaminants on neoplasia development, including breast cancer, has been demonstrated by different studies (Mukherjee et al., 2006; da Fonte de Amorim et al., 2002; Jenkins et al., 2012). The possible role of pyrethroids in altering the homeostasis of hormones such as estrogens and indirectly promoting the neoplastic process
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in mammary epithelial cells has been suggested by Garey and Wolff (1998). Since dogs share the same environment and pollutants with the owners, and their role as sentinel animals is well recognised, further epidemiological studies should be driven to investigate a possible role of carcinogen factors in the study area. As in dogs, breast cancer is the most frequent cancer (31%) diagnosed in women of all age classes, living in Veneto region, with an IR of 176 new cases per 100,000 women (period 2004–2006) (Baracco et al., 2013). Comparing the Veneto registry data with those from the other Italian registries, the breast cancer incidence appears to be higher than the average national IR (Baracco et al., 2013). In the area of the Italian Network of Cancer Registries, during 1998–2002, breast cancer represented 24.9% of all the cancer diagnoses, with an average of 152 new breast cancer diagnoses per 100,000 women per year (http://www.registri-tumori.it/incidenza19982002/rapporto/Schede%20specifiche%20per%20tumore/ Tumore%20della%20mammella%20femminile.pdf). The agestandardized incidence of female breast cancer in Italy was estimated to increase constantly from 43 per 100,000 persons/year in 1970 to approximately 120 per 100,000 persons/year in 2015 (Rossi et al., 2013). Factors that may lead to increases in breast cancer incidence rates include the introduction of populationbased screening using mammography, as well as the increasing prevalence of known risk factors such as obesity, excessive alcohol consumption, reduced physical activity, earlier onset of puberty, and having children at an older age (Youlden et al., 2012). The sharing of some of these risk factors by women and bitches, together with similar IRs and trends observed in dogs and humans, supports the validity of canine MT as an epidemiologic model for human breast cancer. In our survey, the frequency of mammary tumors was significantly associated with age and was less frequent in bitches younger than 6 years, increasing up to approximately 60% for ages between 8 and 13 years. Our data are in accordance with those from other studies that reported a median age of occurrence ranging from 8 to 10 years (Schneider, 1970; Dorn et al., 1968; Hellmén et al., 1993). Data reported by the Norvegian canine cancer project during the years 1990–1998, showed that MT were the third most frequent tumor group in female dogs between 2 and 3.99 years (10%), increasing to 35% in dogs aged 4–5.99 (Gamlem et al., 2008). From 6–13.99 years of age, MTs were the primary tumors in females, ranging from 46% to 50% of all recorded tumors, and decreasing to 40% in dogs over 14 years of age (Gamlem et al., 2008). Our data emphasized a difference in the onset of benign and malignant tumors, with the mean age at diagnosis being significantly higher for malignant tumors (9.74 years) than for benign neoplasms (8.95 years). Similar findings were reported by a recent study where dogs with benign tumors had a mean age of 8.5 years, and dogs with malignant tumors had a mean age of 9.5 years (Sorenmo et al., 2009). Other studies reported that the presence of malignant tumors before 5 years of age is rare (Vail and MacEwen, 2000; Perez Alenza et al., 2000). In women, 89% of breast cancers are diagnosed from the age of 40 onwards (Ferlay et al., 2010). This distribution varies markedly between more developed (95%) and less developed (84%) countries (Ferlay et al., 2010). For women living in Veneto region, breast cancer is the most frequent tumor in all ages, and the 45% of all breast cancers are diagnosed in women between 50 and 69 year of age (Registro tumori Veneto). Keeping in consideration that the canine lifespan is approximately 1/7 that of the human lifespan, the association between age and cancer frequency is strongly comparable between dogs and women. In contrast to dogs, breast cancers in women that develop at a younger age are generally larger, and characterised by a more aggressive behaviour, with rapid progression and a higher mortality rate compared with older women (Axelrod et al., 2008;
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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Fig. 4. Standardized morbidity ratio (SMR) estimates for the most common canine breeds, with the 95% confidence intervals in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Dotted line shows the reference value based on the population average.
Yankaskas, 2005). The current trends of breast cancer in adolescent and young adult women, and the relationship to clinical, social, genetic, and molecular pathologic characteristics have been recently described (Gewefel and Salhia, 2014). Lastly, our study found that the majority of MT (74%) were detected in intact dogs, which were diagnosed at a significantly younger age than spayed dogs (9.20 vs 10.09 years, respectively). It is well known that MT of both dogs and humans are hormonally controlled, and similarities in hormone dependency have been observed between human breast cancer and canine MT (Sleeckx et al., 2011). In women, as in bitches, ovarian steroids stimulate the growth of normal mammary tissue under physiological conditions. In particular, oestrogen promotes ductal growth, whereas progesterone induces a lobuloalveolar development of the mammary glands with hyperplasia of secretory and myoepithelial cells (Rutteman, 1990; Thomas 1984; Queiroga et al., 2005). Interestingly, in our survey, the intact females had a significantly higher proportion of complex carcinoma, which contain cellular elements derived from both secretory and myoepithelial cells, than simple carcinoma. This proportion was reversed in the spayed females. A possible explanation is that during the long luteal phase of the canine oestrous cycle, the mammary gland is exposed to a high concentration of progesterone (Schaefers-Okkens et al., 2005), which may create conditions for neoplastic proliferation. Some prognostic studies suggested that there is an increasing malignancy from complex carcinomas to simple carcinomas (Misdorp et al., 1999; Hellmén et al., 1993; Yamagami et al., 1996; Santos et al., 2013). In human breast cancer, myoepithelial cells exert profound effects on tumor cell behaviour, circumscribing abnormally proliferating breast epithelial cells and separating them from stromal angiogenesis (Barsky and Karlin, 2006). However, during tumor progression, myoepithelial cells seem to loose these properties, and this cell population diminishes as tumors become invasive (Polyak and Hu, 2005). In our survey, purebred dogs had a higher rate of malignant MT than mixed breed dogs. This effect was seen particularly in dogs younger than 7 years, while no significant differences were observed in the oldest age groups. Among purebred dogs, Samoyed, Doberman, Schnauzer and Yorkshire Terrier were more inclined to develop malignant MTs than the overall population average. In
general, purebred dogs were found to be significantly overrepresented among cases of MT and some breeds have been reported to have an increased risk (Schneider 1970; Dorn and Schneider 1976; Egenvall et al., 2005). Although this does not strictly reflect the situation in humans, pure breeds represent a valuable model to investigate the role of genetic features versus environmental risk factors, in the development of cancer. 5. Conclusions Cancer registration represents a key tool for cancer surveillance, estimating the burden of cancer in the population at risk, considering individual and environmental risk factors and monitoring rates of cancer over time. Our study highlights that incidence of MT in dogs living in Veneto region is increasing, and IRs are comparable to that in women. Individual risk factors such as age and breed are associated with tumor development. The great number of epidemiological similarities between dogs and women suggest that spontaneous canine cancers may serve as an important bridge between preclinical studies in mouse model systems and clinical trials in humans, supporting the synergy of collaborations between veterinary and human cancer centers. Conflict of interest None. Acknowledgements The authors are grateful to the veterinary practitioners who participated in the project. References Axelrod, D., Smith, J., Kornreich, D., Grinstead, E., Singh, B., Cangiarella, J., Guth, A.A., 2008. Breast cancer in young women. J. Am. Coll. Surg. 206, 1193–1203. Baracco, M., Bovo, E., Dal Cin, A., Fiore, A.R., Greco, A., Guzzinati, S., Monetti, D., Rosano, A., Stocco, C.F., Tognazzo, S., Zorzi, M., Dei Tos, A.P., 2013. Epidemiologia del tumore della mammella in Veneto. Registro tumori del Veneto, 2–3 http://www.registrotumoriveneto.it/registro/home.php. Barsky, S.H., Karlin, N.J., 2006. Mechanisms of disease: breast tumor pathogenesis and the role of the myoepithelial cell. Nat. Clin. Pract. Oncol. 3, 138–151.
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Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer Marta Vascellari a,∗ , Katia Capello a , Antonio Carminato a , Claudia Zanardello a , Elisa Baioni b , Franco Mutinelli a a b
Istituto Zooprofilattico Sperimentale delle Venezie, Viale dell’università 10, 35020 Legnaro, PD, Italy Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle d’Aosta, Via Bologna, Torino, Italy
a r t i c l e
i n f o
Article history: Received 14 January 2015 Received in revised form 10 February 2016 Accepted 27 February 2016 Keywords: Dog Incidence Mammary tumors Population Risk factors
a b s t r a c t Although mammary gland tumors (MT) are the most-common type of tumor in intact female dogs, there is little information about their incidence in dog population. Data on MT in female dogs was retrieved from the Animal Tumor registry of dogs and cats of Venice and Vicenza provinces during 2005–2013 and was analyzed to visualize crude incidence rates by breed and across age categories. Overall, 2744 mammary tumors were reported accounting for 54% of all tumors in female dogs. The annual incidence rate (IR) was 250 cases per 100,000 dogs. The most frequent malignant tumors were complex carcinomas, consisting of both epithelial and myoepithelial tissues (IR = 71.89), and simple carcinomas (IR = 62.59). The MT incidence rate increased through the study period; particularly in the last 4 years, and malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Seventy-four percent of tumors were diagnosed in intact females, and the mean age at diagnosis was significantly higher for spayed dogs than for intact ones. MT were less frequent in dogs younger than 6 years and increased up to approximately 60% for ages between 8 and 13 years. The purebred dogs had a higher probability to have a malignant neoplasm than mixed-breed dogs, particularly in dogs younger than 7 years, and the Samoyed, Dobermann, Schnauzer and Yorkshire Terrier breeds were more inclined to develop malignant MT. The incidence of MT in dogs is increasing, and IRs are comparable to that in women. The epidemiological similarities between dogs and women support the validity of canine MT as a model for human breast cancer. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Dogs develop mammary gland tumors (MT) spontaneously, and some epidemiologic, clinical, and prognostic features are similar to human breast cancer (Owen, 1979; Misdorp, 2002; Vail and MacEwen, 2000; Mohammed et al., 2011). Despite the fact that MT are the most-common type of tumor in intact female dogs (Sleeckx et al., 2011), there is little information about their incidence in the dog population. Most of the information is based on data obtained from hospitals in which the population is only represented by cases referred to veterinary clinics, or biopsied and necropsied dogs (hospital-based registry). The scarcity of population-based canine registries is partly due to expense and difficulties in acquiring such
∗ Corresponding author. E-mail address: [email protected] (M. Vascellari).
data. Among commonly cited studies, Schneider (1970) reported an incidence of 145 per 100,000 dogs-year at risk amongst female dogs in California, USA. Some European studies showed an incidence rate of approximately 200 per 100,000 dogs-year (Dobson et al., 2002; Merlo et al., 2008; Vascellari et al., 2009). In general, more than 40% of tumors in female dogs are MT (Merlo et al., 2008; Vascellari et al., 2009; Dorn et al., 1968), and approximately 30–50% of canine MT are malignant (Dorn et al., 1968; Sorenmo et al., 2000). Many factors are known to influence the incidence of MT, such as breed, age, and spayed status. Results from different studies showed that the incidence rates of MT in purebred dogs are significantly higher than in mixed-breed (Merlo et al., 2008) and depending on the study, different breeds seem to have an increased risk of developing MT (Jitpean et al., 2012; Moe, 2001; Borge et al., 2011). As in humans, advanced age increases the risk of MT development in dogs, with a median age at diagnosis of approximately 8–10 years (Sleeckx et al., 2011). Furthermore, development of canine MT is hormone
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dependent. Schneider et al. (1969) reported that ovariohysterectomy before the first, second, or third estrus cycle significantly reduces the relative risk of developing MT, while ovariohysterectomy later in life had no significant effect. Breast cancer is also one of the most common cancers in women living in Western countries (Youlden et al., 2012). Excluding skin cancers, breast cancer is the most common malignancy and the second leading cause of cancer death among women in the United States (Desantis et al., 2011). In 2002, the estimated agestandardized rate of breast cancer was equal to 40.4 new cases per 100,000 people worldwide (Parkin et al., 2005), and it increased to 42.3/100,000 in 2008 (Ferlay et al., 2010). After adjusting the number of new cases for population size and age, it emerged that incidence rates were almost 2.5 times higher in the more developed countries than in less developed ones (71.7/100,000 and 29.3/100,000, respectively) (Ferlay et al., 2010). A range of factors relating to lifestyle in more developed countries, such as having fewer children, giving birth at an older age and being less likely to breastfeed, may influence the incidence rate. Higher levels of obesity combined with lower levels of physical activity, increased alcohol consumption, and use of oral contraceptives and hormone replacement therapies, may also affect incidence (Youlden et al., 2012). Globally, 89% of breast cancers are diagnosed from the age of 40 onwards (Ferlay et al., 2010; Youlden et al., 2012). The main objective of this study was to describe the incidence of MT in female dogs living in the Venice and Vicenza provinces during 2005–2013 and to measure the incidence by breed and across age categories. The descriptive epidemiological data obtained have been compared with those obtained by the human cancer registries in the same area and globally.
while the recapture sample was obtained by a telephone survey of households of the Veneto Region (Capello et al., 2015). The canine population estimated in 2011, was 137.006 (95% CI 127.603–149.302), and it has been considered stable through the study period. The lower and upper limits of the 95% confidence interval of the population estimate were used as the denominator to provide the intervals of the IRs, later called “range”. The trend of IRs during the study period was evaluated after having split the observation period into 4 periods of 24 months each. The chi-squared test was used to compare the proportion of benign and malignant tumors and the proportion of complex and simple carcinomas during the study period. The Student’s t-test was used to assess differences in the mean age between dogs with malignant and benign tumors and between neutered and entire subjects. The Satterthwaite approximation was used to allow for variance heterogeneity. A logistic regression analysis was used to evaluate the association of spayed status, age, breed (pure and mixed-breed), and their interaction on the occurrence of malignant and benign tumors. The same statistical method was applied to malignant tumors and, particularly, to compare complex versus simple carcinoma (other types of malignant neoplasms were not considered in the analysis, given the low number of cases). For both models, the p-values obtained using type 3 analysis were used to evaluate the significance of the main effects. The odds ratios (OR) with 95% confidence intervals (95%CI) were used to summarize the results. To assess the distribution of cases among breeds, standardized morbidity ratios (SMRs) with 95% confidence intervals were calculated using the Canine Demographic Registry of the Veneto region as the reference population for the distribution of breeds in the general dog population. The SMR for a specific breed was obtained using o /C the formula: SMRb = nb /N where ob and nb are the number of cases
2. Material and methods
and the number of dogs for a specific breed, respectively, while C and N are the total number of cases in the ATR and the number of dogs in the reference population, respectively.
b
In April 2005 the Animal Tumor Registry (ATR) of Vicenza and Venice provinces of Veneto region (northern Italy) was established (Vascellari et al., 2009). This incidence registry, is based on an active surveillance program and includes both malignant and benign neoplasia. A network of collaboration with the veterinary clinics in Veneto region was established, inviting to submit any suspected neoplasm from dogs and cats living in the Vicenza and Venice provinces. The histopathology lab of the IZSVe, provides free cytological and histopathological evaluation to practitioners in the area of the registry. A standardized case-report form, specifically designed for the collection of canine and feline tumor cases, was made available to all veterinarians (Vascellari et al., 2009). MTs were classified according to the World Health Organization International histological classification of tumors of domestic animals (Misdorp et al., 1999), in order of malignancy in the following types: non infiltrating (in situ) carcinoma, complex carcinoma, simple carcinoma (tubulopapillary, solid, anaplastic), special types of carcinoma (spindle cell carcinoma, squamous cell carcinoma, mucinous carcinoma, lipid-rich carcinoma), sarcoma (fibrosarcoma, osteosarcoma), and carcinosarcoma. Benign tumors were classified into simple and complex adenoma, basaloid adenoma, fibroadenoma, benign mixed tumor, and duct papilloma. 2.1. Statistical analysis Crude and specific incidence rates (IRs) were calculated by dividing the number of cases by the estimate of the canine population of the registry catchment area, multiplied by the number of years. The estimate of the canine population was obtained by applying the Lincoln-Petersen version of the capture-recapture method (Seber, 1982): the capture sample was represented by the official Canine Demographic Registry established in Veneto region,
3. Results Overall 2744 MT were reported in 2359 dogs, accounting for 33% of all tumors in the whole population, and 54% in females. The annual incidence rate was 250 cases per 100,000 dogs, ranging from 229.74 to 268.80 per 100,000 dogs, given the confidence interval of the population estimate. Malignant tumors (1636, 60%, IR = 149.26 range: 136.97–160.26) were more frequent than benign neoplasms (1108, 40%, IR = 101.09 range: 92.77–108.54). The most frequent malignant tumors were complex carcinomas consisting of both epithelial and myoepithelial tissues (788, IR = 71.89, range: 65.97–77.19), and simple carcinoma (686, IR = 62.59, range: 57.43–67.20). Other tumors were special types of carcinoma (61, IR = 5.57, range: 5.11–5.98), carcinosarcoma (24, IR = 2.19, range: 2.01–2.35) and in situ carcinoma (17, IR = 1.55, range: 1.42–1.67). Fifty-eight tumors of mesenchymal origin (fibrosarcoma/osteosarcoma/other sarcomas) were collected (IR = 5.29, range: 4.86–5.68). Among benign tumors the most frequent were complex adenoma (485, IR = 44.25, range: 40.61–47.51), simple adenoma (320, IR = 29.20, range: 26.79–1.35) and mixed benign tumors, which are a combination of epithelial and mesenchymal tissues (251, IR = 22.90, 95%CI: 21.01–24.59). The MT incidence rate increased through the study period (Fig. 1), ranging from 178.82 (range: 164.10–192.00) to 313.12 (range: 287.34–336.20). A significant association between the classification of benign and malignant tumors and the 4 investigated periods was observed (pvalue < 0.001, Table 1), highlighting different trends between the two groups of tumors. At the end of the study period, malignant neoplasms occurred more frequently (70%) than the benign counterparts (30%). Focusing on the most frequent types of malignant
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Table 1 Number (n) and percentage (%) of benign and malignant tumors during the study period, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Type of neoplasm
Mammary tumors Benign Malignant Complex carcinoma Simple carcinoma Other malignant
April 2005–March 2007
April 2007–March 2009
April 2009–March 2011
April 2011–March 2013
Total
n
%
n
%
n
%
n
%
n
%
490 182 308 134 140 34
37.1 62.9 43.5 45.5 11.0
594 299 295 130 126 39
50.3 49.7 44.1 42.7 13.2
802 366 436 206 193 37
45.6 54.4 47.2 44.3 8.5
858 261 597 318 227 52
30.4 69.6 53.3 38.0 8.7
2744 1108 1636 788 686 162
40.4 59.6 48.1 41.9 10.0
Fig. 1. Trend of the incidence rates through the study period in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy); the error bars shows the intervals of the incidence rates, calculated using the lower and upper limits of the 95% confidence intervals of the population estimate.
MT, complex and simple carcinomas, a significant difference in the distribution of cases during the study period was noted (p-value 0.032), which principally resulted from the increase of complex carcinoma cases in the last two years. Spayed status, breed and age of tumor cases are shown in Table 2, while Table 3 reports the results of logistic regression analyses. Six hundred and ninety four (26%) tumor cases were detected in spayed subjects. The mean age at diagnosis was significantly higher
(p-value < 0.001) for spayed dogs (10.09 years, sd 2.57) than for intact females (9.20 years, sd 2.63). No significant differences in the proportion of malignant tumors were observed between spayed (60%) and intact dogs (58%). However, complex carcinoma occurred in a smaller proportion of the spayed dogs (43%) compared with simple carcinoma (57%). The opposite trend was seen in intact females (p = 0.007), providing an OR of 0.62 (95%IC: 0.44–0.88).
Table 2 Number (n) and percentage (%) of mammary tumors according to the spayed status, breed and age groups, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Mammary tumors Benign
Total Spayed status Entire Neutered NA Breed Pure breed Mixed breed NA Age (years) 0–3 4–5 6–7 8–9 10–11 12–13 14+ NA
Types of malignant neoplasms Malignant
Simple carcinoma
Complex carcinoma
Other types of carcinoma
n
%
n
%
n
%
n
%
n
%
1108
40.4
1636
59.6
686
41.9
788
48.2
162
9.9
828 268 12
41.1 38.6 34.3
1187 426 23
58.9 61.4 65.7
465 212 9
39.2 49.8 39.1
622 156 10
52.4 36.6 43.5
100 58 4
8.4 13.6 17.4
666 440 2
39.1 42.7 22.2
1038 591 7
60.9 57.3 77.8
436 244 6
42.0 41.3 85.7
506 281 1
48.7 47.5 14.3
96 66 0
9.2 11.2 0.0
28 76 199 322 273 145 42 23
60.9 62.3 48.4 43.4 37.9 33.7 30.9 16.8
18 46 212 420 447 285 94 114
39.1 37.7 51.6 56.6 62.1 66.3 69.1 83.2
8 22 70 157 179 144 49 57
44.4 47.8 33.0 37.4 40.0 50.5 52.1 50.0
8 22 132 227 220 100 32 47
44.4 47.8 62.3 54.0 49.2 35.1 34.0 41.2
2 2 10 36 48 41 13 10
11.1 4.3 4.7 8.6 10.7 14.4 13.8 8.8
NA: not available.
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Table 3 Chi-square values and p-values for the significance of the spayed status, breed, age groups and their interactions, obtained by logistic regression (LR) analyses in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Effect
Breed Age groups Spayed status Breed × Spayed status Age classes × Spayed status Breed × Age groups
LR for malignant vs benign neoplasms
LR for complex vs simple carcinoma
Chi-Square
Pr > ChiSq
Chi-Square
Pr > ChiSq
7.89 46.17 1.37 0.65 5.05 13.55
0.005 <0.0001 0.2411 0.4218 0.4099 0.0188
1.72 22.15 7.29 0.46 4.93 8.25
0.1892 0.0005 0.0069 0.4987 0.4246 0.143
Fig. 2. Percentages of mammary tumors vs. other tumors in female dogs among different age groups, in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy).
Fig. 3. Trend of incidence rates according to the age of diagnosis in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy); the error bars shows the intervals of the incidence rates, calculated using the lower and upper limits of the 95% confidence intervals of the population estimate.
The frequency of MT had a significant association with age groups (p < 0.001), and MT were less frequent in the first two age groups ( < 6 years) and increased up to approximately 60% for ages between 8 and 13 years (Fig. 2). In particular, a statistically significant increase (p < 0.001) in malignant tumors among age groups was noted, ranging from 39% to 69% in the youngest and oldest age group, respectively. The mean age at diagnosis was significantly higher (p < 0.001) for malignant tumors (9.74 years, sd 2.60) than for benign neoplasms (8.95 years, sd 2.66). Differences in the age at diagnosis between the two groups of tumors were noticeable in the age-specific incidence rates (Fig. 3). Moreover, the complex
carcinoma cases were diagnosed at younger ages (p < 0.001, 9.34 years, sd 2.44) than simple carcinoma cases (10.04 years, sd 2.71); in particular, dogs younger than 11 years were approximately 2 times more likely to develop a complex carcinoma (OR = 1.99, 95%CI: 1.45–2.75) than older dogs. Overall 1704 (62%) tumor cases were reported in purebred dogs with an IR of 282.67 (range: 259.39–303.50), and 1031 (38%) cases were reported in mixed-breed dogs with an IR of 209.03 (range: 259.39–303.50). A significant interaction between breed and age regarding the development of malignant versus benign tumors was observed (p-value 0.016), as reported in Table 4. The purebred dogs
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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M. Vascellari et al. / Preventive Veterinary Medicine xxx (2016) xxx–xxx Table 4 Proportion and Odds Ratio (OR) with the 95% confidence interval (95%CI) of malignant mammary tumors in pure breed dogs when compared to mixed breeds stratified by age class in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Age classes (years)
0–5 6–7 8–9 10–11 12–13 14+
% of malignant tumors Pure breed
Mixed breed
44.74 57.79 57.45 64.02 65.53 72.22
23.53 36.97 53.33 59.09 67.42 68.00
OR
95% CI
2.63 2.34 1.18 1.23 0.92 1.22
1.25–5.54 1.53–3.63 0.86–1.62 0.90–1.68 0.61–1.37 0.53–2.48
were approximately 2 times more likely than mixed-breed dogs to have a malignant neoplasm in both the age groups of 0–5 years (OR: 2.63, 95%CI: 1.25–5.54) and 6–7 years (OR: 2.34, 95%CI: 1.53–3.63). For the oldest age groups (>7 years), no differences between pure and mixed breed were found. In Fig. 4, the SMRs on malignant tumors by breed are reported. The Samoyed dogs were approximately twice as likely to develop malignant MT than the overall population, and were followed by Doberman, Schnauzer and Yorkshire Terrier with SMRs between 2 and 1.5. Conversely, the English Setter, Golden Retriever and Labrador Retriever had SMRs of 0.50, 0.36 and 0.36, respectively, indicating that the probability to develop a malignant MT for these breeds is lower than the population average. 4. Discussion The aim of this study was to provide descriptive epidemiological data on MT in female dogs living in Venice and Vicenza provinces, keeping in consideration incidence trends and individual risk factors. In fact, even though MT are one of the most frequent tumors in dogs, few population-based epidemiological studies are available (Dorn et al., 1968; Moe, 2001; Merlo et al., 2008; Vascellari et al., 2009; Brønden et al., 2010). The proportion of MT among other types of tumor was 33% in the whole population, and 54% in females. MT have the second highest incidence in the animal tumor registry of Vicenza and Venice provinces (IR 250 cases per 100,000 dogs ranging from 229.74 to 268.80). Malignant MT showed an IR of 149 new cases per 100,000 dogs/year, showing an increasing trend, particularly in the last two years. Since the registered cases were provided by veterinary practitioners on a voluntary basis, the estimated incidence could has been underestimated. The completeness of submissions in the catchment area was sought maximized by a capillary and continuous information of the veterinarians as well as providing the histopathological investigation free of charge. Other factors that might influence the results from the registry are the likelihood of dogs being brought to a veterinarian and willingness of the owner to pursue (and pay for) a diagnostic work-up for their dog. Unfortunately, these factors are hard to be estimated. Factors that may have led to the increase of MT incidence rates are the stabilization of the registry in the study area, leading to an increasing trend of sample submission, as well as the improvement of owners and veterinary care. However, it is worth noting that the increase of IRs is primarily associated with malignant tumors, while the IRs of benign neoplasms seems to decrease. Giving that no changes occurred in the diagnostic criteria during the study period (classification system, pathologists) other factors should be considered to explain this trend. The influence of environmental contaminants on neoplasia development, including breast cancer, has been demonstrated by different studies (Mukherjee et al., 2006; da Fonte de Amorim et al., 2002; Jenkins et al., 2012). The possible role of pyrethroids in altering the homeostasis of hormones such as estrogens and indirectly promoting the neoplastic process
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in mammary epithelial cells has been suggested by Garey and Wolff (1998). Since dogs share the same environment and pollutants with the owners, and their role as sentinel animals is well recognised, further epidemiological studies should be driven to investigate a possible role of carcinogen factors in the study area. As in dogs, breast cancer is the most frequent cancer (31%) diagnosed in women of all age classes, living in Veneto region, with an IR of 176 new cases per 100,000 women (period 2004–2006) (Baracco et al., 2013). Comparing the Veneto registry data with those from the other Italian registries, the breast cancer incidence appears to be higher than the average national IR (Baracco et al., 2013). In the area of the Italian Network of Cancer Registries, during 1998–2002, breast cancer represented 24.9% of all the cancer diagnoses, with an average of 152 new breast cancer diagnoses per 100,000 women per year (http://www.registri-tumori.it/incidenza19982002/rapporto/Schede%20specifiche%20per%20tumore/ Tumore%20della%20mammella%20femminile.pdf). The agestandardized incidence of female breast cancer in Italy was estimated to increase constantly from 43 per 100,000 persons/year in 1970 to approximately 120 per 100,000 persons/year in 2015 (Rossi et al., 2013). Factors that may lead to increases in breast cancer incidence rates include the introduction of populationbased screening using mammography, as well as the increasing prevalence of known risk factors such as obesity, excessive alcohol consumption, reduced physical activity, earlier onset of puberty, and having children at an older age (Youlden et al., 2012). The sharing of some of these risk factors by women and bitches, together with similar IRs and trends observed in dogs and humans, supports the validity of canine MT as an epidemiologic model for human breast cancer. In our survey, the frequency of mammary tumors was significantly associated with age and was less frequent in bitches younger than 6 years, increasing up to approximately 60% for ages between 8 and 13 years. Our data are in accordance with those from other studies that reported a median age of occurrence ranging from 8 to 10 years (Schneider, 1970; Dorn et al., 1968; Hellmén et al., 1993). Data reported by the Norvegian canine cancer project during the years 1990–1998, showed that MT were the third most frequent tumor group in female dogs between 2 and 3.99 years (10%), increasing to 35% in dogs aged 4–5.99 (Gamlem et al., 2008). From 6–13.99 years of age, MTs were the primary tumors in females, ranging from 46% to 50% of all recorded tumors, and decreasing to 40% in dogs over 14 years of age (Gamlem et al., 2008). Our data emphasized a difference in the onset of benign and malignant tumors, with the mean age at diagnosis being significantly higher for malignant tumors (9.74 years) than for benign neoplasms (8.95 years). Similar findings were reported by a recent study where dogs with benign tumors had a mean age of 8.5 years, and dogs with malignant tumors had a mean age of 9.5 years (Sorenmo et al., 2009). Other studies reported that the presence of malignant tumors before 5 years of age is rare (Vail and MacEwen, 2000; Perez Alenza et al., 2000). In women, 89% of breast cancers are diagnosed from the age of 40 onwards (Ferlay et al., 2010). This distribution varies markedly between more developed (95%) and less developed (84%) countries (Ferlay et al., 2010). For women living in Veneto region, breast cancer is the most frequent tumor in all ages, and the 45% of all breast cancers are diagnosed in women between 50 and 69 year of age (Registro tumori Veneto). Keeping in consideration that the canine lifespan is approximately 1/7 that of the human lifespan, the association between age and cancer frequency is strongly comparable between dogs and women. In contrast to dogs, breast cancers in women that develop at a younger age are generally larger, and characterised by a more aggressive behaviour, with rapid progression and a higher mortality rate compared with older women (Axelrod et al., 2008;
Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008
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Fig. 4. Standardized morbidity ratio (SMR) estimates for the most common canine breeds, with the 95% confidence intervals in a study on mammary tumors in dogs living in the Venice and Vicenza provinces (Veneto region, Italy). Dotted line shows the reference value based on the population average.
Yankaskas, 2005). The current trends of breast cancer in adolescent and young adult women, and the relationship to clinical, social, genetic, and molecular pathologic characteristics have been recently described (Gewefel and Salhia, 2014). Lastly, our study found that the majority of MT (74%) were detected in intact dogs, which were diagnosed at a significantly younger age than spayed dogs (9.20 vs 10.09 years, respectively). It is well known that MT of both dogs and humans are hormonally controlled, and similarities in hormone dependency have been observed between human breast cancer and canine MT (Sleeckx et al., 2011). In women, as in bitches, ovarian steroids stimulate the growth of normal mammary tissue under physiological conditions. In particular, oestrogen promotes ductal growth, whereas progesterone induces a lobuloalveolar development of the mammary glands with hyperplasia of secretory and myoepithelial cells (Rutteman, 1990; Thomas 1984; Queiroga et al., 2005). Interestingly, in our survey, the intact females had a significantly higher proportion of complex carcinoma, which contain cellular elements derived from both secretory and myoepithelial cells, than simple carcinoma. This proportion was reversed in the spayed females. A possible explanation is that during the long luteal phase of the canine oestrous cycle, the mammary gland is exposed to a high concentration of progesterone (Schaefers-Okkens et al., 2005), which may create conditions for neoplastic proliferation. Some prognostic studies suggested that there is an increasing malignancy from complex carcinomas to simple carcinomas (Misdorp et al., 1999; Hellmén et al., 1993; Yamagami et al., 1996; Santos et al., 2013). In human breast cancer, myoepithelial cells exert profound effects on tumor cell behaviour, circumscribing abnormally proliferating breast epithelial cells and separating them from stromal angiogenesis (Barsky and Karlin, 2006). However, during tumor progression, myoepithelial cells seem to loose these properties, and this cell population diminishes as tumors become invasive (Polyak and Hu, 2005). In our survey, purebred dogs had a higher rate of malignant MT than mixed breed dogs. This effect was seen particularly in dogs younger than 7 years, while no significant differences were observed in the oldest age groups. Among purebred dogs, Samoyed, Doberman, Schnauzer and Yorkshire Terrier were more inclined to develop malignant MTs than the overall population average. In
general, purebred dogs were found to be significantly overrepresented among cases of MT and some breeds have been reported to have an increased risk (Schneider 1970; Dorn and Schneider 1976; Egenvall et al., 2005). Although this does not strictly reflect the situation in humans, pure breeds represent a valuable model to investigate the role of genetic features versus environmental risk factors, in the development of cancer. 5. Conclusions Cancer registration represents a key tool for cancer surveillance, estimating the burden of cancer in the population at risk, considering individual and environmental risk factors and monitoring rates of cancer over time. Our study highlights that incidence of MT in dogs living in Veneto region is increasing, and IRs are comparable to that in women. Individual risk factors such as age and breed are associated with tumor development. The great number of epidemiological similarities between dogs and women suggest that spontaneous canine cancers may serve as an important bridge between preclinical studies in mouse model systems and clinical trials in humans, supporting the synergy of collaborations between veterinary and human cancer centers. Conflict of interest None. Acknowledgements The authors are grateful to the veterinary practitioners who participated in the project. References Axelrod, D., Smith, J., Kornreich, D., Grinstead, E., Singh, B., Cangiarella, J., Guth, A.A., 2008. Breast cancer in young women. J. Am. Coll. Surg. 206, 1193–1203. Baracco, M., Bovo, E., Dal Cin, A., Fiore, A.R., Greco, A., Guzzinati, S., Monetti, D., Rosano, A., Stocco, C.F., Tognazzo, S., Zorzi, M., Dei Tos, A.P., 2013. Epidemiologia del tumore della mammella in Veneto. Registro tumori del Veneto, 2–3 http://www.registrotumoriveneto.it/registro/home.php. Barsky, S.H., Karlin, N.J., 2006. Mechanisms of disease: breast tumor pathogenesis and the role of the myoepithelial cell. Nat. Clin. Pract. Oncol. 3, 138–151.
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Please cite this article in press as: Vascellari, M., et al., Incidence of mammary tumors in the canine population living in the Veneto region (Northeastern Italy): Risk factors and similarities to human breast cancer. PREVET (2016), http://dx.doi.org/10.1016/j.prevetmed.2016.02.008