- Email: [email protected]
The Epidemiology and Incidence of Cancer
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CHAPTER
4
The Epidemiology and Incidence of Cancer John S. Reif
T
here is good evidence to support the statement that cancer is an important disease of dogs and cats at all ages and the leading cause of death in older pet animals. However, developing precise estimates of cancer morbidity and mortality rates in pet animals has been difficult to achieve. When compared to human cancer epidemiology, conducting epidemiologic studies of cancer in dogs and cats is limited by three key data gaps. First, the lack of a census for pet animals precludes measuring morbidity and mortality rates directly, since the population from which the cases originate is generally unknown. In 2001, there were an estimated 73.9 million dogs and 90.5 million cats living in all households in the United States.1 Over 63% of all households reported owning at least one pet during 2005. Eighty-five percent of dogowning households reported taking their dog to a veterinarian in that year, with an average of 1.8 visits per dog. Second, case ascertainment is incomplete and subject to various forms of bias. Since the diagnosis of cancer may require special procedures and diagnostic tests including radiography, ultrasound, and biopsy, not all cases of cancer that are presented to veterinary practices are diagnosed equally. Further, because of the relatively high costs for many advanced diagnostic procedures and treatments, some owners may elect to euthanize pets, especially older animals, without a biopsy or a definitive diagnosis. Third, since death certificates are not required, estimation of mortality has been restricted to relatively few studies where suitable population denominators existed. Similarly, to calculate incidence rates one needs data about the population from which the cases are drawn. For human epidemiology, the creation of state-based cancer registries with comprehensive, mandatory reporting from physicians, hospitals, and diagnostic laboratories has permitted the calculation of population-based incidence rates using census data in denominators. Cancer registries are an invaluable source of data for measuring risk and for comparing cancer incidence over time and from place to place. Most studies of the epidemiology of cancer in pets have been forced to rely on surrogate data sources to estimate 68
morbidity and mortality rates, since population-based data are not readily available.
DESCRIPTIVE EPIDEMIOLOGY Descriptive epidemiology is the first phase of investigation in which disease is described according to three features: the person or animal affected, time, and place. Descriptive epidemiology is used to generate hypotheses regarding potential associations with a variety of exposures, some of which may lie in the causal pathway to disease. Therefore, descriptive studies are essential for understanding the occurrence of cancer in pet animals and setting the stage for testing hypotheses regarding potential causal factors. Hypothesis testing will be discussed later in this chapter under the heading Analytic Epidemiology. Understanding the risk factors for cancer is critical for developing preventive strategies aimed at reducing the risk of developing cancer. Cancer prevention is at its infancy in veterinary medicine and has had only limited success in human medicine. Screening programs for high-risk individuals in human and veterinary oncology may identify cancer at an early stage when the likelihood of treatment success is highest. Rates of disease are calculated to describe the occurrence of cancer in animal or human populations. Morbidity rates estimate the number of new cases of cancer in the population (incidence rates) or existing cases of cancer in the population (prevalence rates), while mortality rates describe deaths from cancer in the population over a suitable time period.
MORBIDITY RATES Cancer Incidence Rates The incidence rate (sometimes referred to incorrectly as “incidence”) of cancer is measured as the number of new cases of cancer developing in a defined
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Chapter 4 • The Epidemiology and Incidence of Cancer population per unit of time such as 1 year. Age-, sex-, and breed-specific incidence rates provide detailed information about the occurrence of cancer in specific segments of the population and are important elements of descriptive epidemiology. Unfortunately, incidence rates for canine and feline cancer are difficult to measure since population-based registries do not exist. Despite this limitation, several studies have been able to calculate incidence rates for canine and feline cancers.
The Alameda and Contra Costa Counties Animal Neoplasm Registry The most comprehensive effort to estimate cancer incidence rates was conducted in a survey of veterinary practices in Alameda and Contra Costa counties (in California) from 1963 to 1966. Dorn et al. attempted to identify all neoplasms diagnosed by enlisting the cooperation of 65 veterinary practices in the two Bay Area counties and 11 practices in contiguous counties that treated animals from Alameda and Contra Costa counties.2 The investigators encouraged participating veterinarians to submit tissue from all suspected cases of neoplasia in return for a free histologic diagnosis. The denominator was estimated by conducting a survey in a probability sample of households in Alameda County to derive the age, sex, and breed distribution of pets and to determine whether the household had used veterinary services. A denominator of dogs and cats from “veterinary using households” was created for the calculation of incidence rates. An estimated annual incidence rate of 3.8 cases of cancer per 1000 dogs was calculated (381/100,000), indicating that almost 4 dogs per 1000 living in households that used veterinary services have a newly diagnosed case of cancer each year. The incidence rate for all cancer in cats was 155.8/100,000. Although this study is badly outdated and many limitations of the data exist due to incomplete ascertainment associated with the diagnostic practices in use in the 1960s and changes in breed distribution since publication, it remains the seminal study for estimating the incidence of canine and feline cancer.3
The Tulsa Registry of Canine and Feline Neoplasms The Tulsa Registry of Canine and Feline Neoplasms was the second animal tumor registry in the United States.4 Histologically confirmed tumors were included in the numerators for calculations of total incidence rate, for rates for benign and malignant neoplasms, and for specific cancer incidence rates. The population at risk was derived by counting all animals seen at all of the 35 participating animal hospitals during the first 2 registry years to estimate the “veterinary-using” population. Among the 63,504 dogs seen by participating veterinarians during the first year, 715 had one or more tumors for an
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incidence rate of 1126 per 100,000. Among 11,909 cats, 56 had at least one tumor for an incidence of 470 cases per 100,000. Tumors of the skin were the most frequently diagnosed neoplasms, as was the case for the California registry study. Note that these rates are about three times higher than those reported for California, due mainly to differences in the method of estimating the denominator.
Studies of Insured Dogs Several studies of morbidity and mortality in insured dogs in Sweden have been published.5,6,7 Data from these studies are derived from observations on more than 200,000 dogs insured by one Swedish company and are believed to represent approximately one third of all Swedish dogs.5 Approximately 50% of Swedish dogs are insured for veterinary care, and approximately two thirds of these are insured by a single company.6 Dogs were insured for life insurance or for veterinary care. Unfortunately from the standpoint of cancer epidemiology, dogs were only eligible for life insurance initially up to the age of 10 years5 and more recently until age 11.7 Few older dogs are covered for veterinary care. Morbidity rates were based on accessions for veterinary care that exceeded a deductible sum (approximately $100). It is not known to what extent insured dogs represent the total population of dogs. Despite these limitations, this database allowed the investigators to calculate overall morbidity and mortality rates for cancer in dogs as well as age-, sex-, and breed-specific rates. The risk for morbidity due to neoplasia was 2.66% among females, 1.58% among males, and 2.13% overall.7 In one publication, the incidence rate of mammary tumors was determined to be 111 per 10,000 dog-years at risk (DYAR).8 The mortality rate for mammary tumors was six deaths per 10,000 DYAR. High-risk breeds (e.g., English springer spaniel, Doberman pinscher, boxer) were identified from the Swedish insurance data. The rates were not adjusted for neuter status but most female dogs in Sweden are not neutered.8
Studies of Military Working Dogs The population of working dogs maintained by the U.S. Department of Defense has also provided an opportunity to study the lifetime incidence of neoplasia and causes of death.9 Approximately 1700 working dogs make up this cohort, which consists primarily of Belgian shepherd dogs (61.5%) and German shepherd dogs (30.6%).10 Among this population of primarily intact male dogs, the lifetime incidence of neoplasia exceeded 30%, with 10% developing more than one neoplasm. Seminoma of the testicle was the most frequently occurring malignancy.9 Although the data are restricted mainly to two breeds, the extensive medical surveillance and necropsy examination that are applied routinely make this dataset of interest.
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Cancer Prevalence Rates Prevalence is the proportion of existing cases of cancer in a population at a single point in time (point prevalence) or over a period of time such as 1 year (period prevalence). Cancer prevalence has been estimated for canine and feline cancers using several types of populations as the denominator. Prevalence estimates have been based on necropsy series,11,12 diagnostic laboratory accessions,13 examination of dogs from pounds,14 single veterinary teaching hospitals,15 a group of veterinary teaching hospitals16 and surveys of breed club members (Bernese Mountain Dog Club, Golden Retriever Foundation)17,18 and dog owners.19 It is critical to consider the population denominator from which the cases of cancer were identified in order to understand the strengths and limitations of the data. None of the populations described is population-based. The denominators used do not represent the population of dogs or cats at large; therefore, estimates of prevalence obtained from these data are subject to selection bias. Nonetheless, usable information can be gleaned from these sources that permit estimation of prevalence adequate to describe general features of the distribution of canine and feline cancer. For example, the high risk of cancer in the boxer dog was first identified in 1959 by examining two case series of malignant lymphoma obtained from 130 participating veterinarians and dog registration data.20 These findings were confirmed in a series of diagnostic laboratory accessions,13 by examining data from the University of Pennsylvania veterinary teaching hospital,15 and with data from the Veterinary Medical Data Program and a series of hospital accessions.21 Boxer dogs were also identified as a high-risk breed for malignant lymphoma in the Alameda and Contra Costa counties animal neoplasm registry.22
The Veterinary Medical Data Base (VMDB) The VMDB was initiated in 1964 by the National Cancer Institute for the purpose of studying cancer in animals. The program was based on collecting standardized abstracts of descriptive, diagnostic, and surgical data from the records of animals seen at participating North American veterinary teaching hospitals. The program began with the recruitment of 11 hospitals and now includes 26 universities that have collectively submitted more than 7 million records to this database. Data from the VMDB have been used for numerous descriptive and analytical epidemiological studies. These investigations have been limited by the small number of potential risk factors included on the abstract but have been useful for identifying risks for numerous types of cancer associated with age, sex, breed, and neutering status. The data have been used rarely to examine geographic differences in cancer prevalence.23 Lack of data for diet, residential history, and specific environmental exposures has
precluded the exploration of specific etiologic hypotheses. However, an extensive series of papers published with VMDB data has permitted the characterization of cancer risk by age, sex, and breed for many canine and feline cancers including tumors of the bone,24 lymphatic system,21 skin,25 pancreas,26 nervous system,28 thyroid,27 mouth and pharynx,29 bladder,30 testicle,31 nasal cavity and paranasal sinuses,32 kidney,33 ovary,34 and mammary gland.35 Despite changes in the distribution of specific breeds of dogs and cats, neutering practices, and longevity over time, data from these studies remain the basis of our understanding of the descriptive epidemiology of many canine and feline tumors. The fundamental weakness in these data is their hospital-based nature and the potential for the introduction of selection bias from nonrepresentative numerator and denominator data.
Survey Data Several surveys of animal owners have been published that provide a crude estimate of the prevalence of various disorders and causes of death. Danish investigators queried members of the Danish Kennel Club in 1997 and received information for 4295 dogs.36 The kennel club represents approximately 53% of all registered dogs in Denmark where registration is compulsory. Tumors accounted for 4.4% of all reported diseases. Higher breedspecific prevalence rates of neoplasia were reported for the English springer spaniel, Hovawart, Samoyed, flatcoated retriever, golden retriever, and beagle, but specific causes of neoplasia were not identified. These authors also described owner-reported causes of mortality for 2928 dogs from the same source population.37 The proportionate cancer mortality was 14.5% (cancer deaths divided by all causes of death). High prevalence of death due to cancer was reported for the Bernese mountain dog, flatcoated retriever, and beagle. Since the data from these studies are self-reported and not confirmed by medical record validation, they are of limited usefulness, despite having a population-based origin. In the United States, several surveys of breed club members have been undertaken. The Golden Retriever Club of America conducted a national health survey of its membership in 1998 and described the findings for more than 1440 dogs.18 The lifetime risk of a golden retriever developing a neoplasm was 50%. Hemangiosarcoma was the most frequently reported cancer with a lifetime risk of 1 in 5, followed by malignant lymphoma with a lifetime risk of 1 in 8. This study separated diagnoses confirmed by a veterinarian from those reported by the owner only. Members of the Bernese Mountain Dog Club confirmed the importance of cancer in this breed in a survey.17 Cancer deaths represented 49% of 261 deaths. Malignant histiocytosis was the most frequent type of cancer in this breed, confirming earlier published reports.38 Finally, Mark Morris Associates conducted an animal health survey in 1998 by mail-back questionnaire
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Chapter 4 • The Epidemiology and Incidence of Cancer in its newsletter. Despite a poor response rate (2.7%), 2003 responses were received. Cancer was listed as the leading cause of death among dogs (47%) and cats (32%).19
MORTALITY RATES Cancer Proportional Mortality Rates Mortality from cancer in dogs and cats has been reported infrequently. The most common source of mortality data is the cancer proportional mortality rate (CPMR). In calculating the CPMR, the number of animals that died from cancer is divided by the number dying of all causes. Typically such data are found in series of necropsied cases. The main shortcoming from such analyses is that the proportion depends not only on the frequency of cancer as a cause of death but on the frequency of all other disorders in the database. Proportionate mortality analyses are prone to selection bias due to the patterns of referral of the institution, the probability that a necropsy will be performed, special interests of the staff, and so on. Many early descriptions of cancer in pet animals were based on series of necropsy examinations and used to infer data for incidence rates with obvious limitations.11,12 A study of 2002 dogs necropsied at the Angell Memorial Animal Hospital found that cancer accounted for 20% of the deaths at 5 years and increased to over 40% in dogs 10 years of age and older, thus supporting the contention that cancer is the leading cause of death among older dogs.39 Another study assessed the CPMR among 1206 golden retrievers, boxers, German shepherd dogs, Labrador retrievers and rottweilers.40 The CPMRs for golden retrievers and boxers were significantly higher than those for the other breeds. The highest CPMR was found for golden retrievers (56.6%), followed by the boxer (51.9%), and German shepherd dog (36.7%). The lowest CPMR was for the rottweiler (28.2%). These data illustrate the importance of cancer as a cause of death even among lower-risk breeds. The age at death was not significantly different among the five breeds, reducing the possibility that confounding by age played an important role in the findings. Ideally, mortality data should be obtained from longitudinal, prospective studies of dog populations or representative samples of these populations. As cohort studies become more commonplace in pet animals, valid mortality data may become available. One potential source of such data is a national database representative of dogs examined by small animal veterinarians and reported systematically by electronic communication.41 The potential usefulness of such a system has been validated by a study assessing the frequency of postvaccinal reactions and vaccine site-associated sarcomas in cats.42 Data from large populations of dogs identified through
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a national surveillance system represent an additional potential source of mortality data.43 Finally, clinical descriptions of death rates among dogs with cancer (dogs dieing of cancer/dogs with cancer) are often referred to as “mortality” rates. These rates are more properly referred to as “case fatality rates” but the usage has become widely accepted.
Adjusted Rates When rates are compared between breeds, sexes, neuter status, geographic location, and other factors, it is important to consider the possibility that confounding may be responsible for observed differences. The risk of most cancers is related to age. Therefore, differences in the age distribution between groups of dogs may introduce bias due to confounding. Standard methods exist for adjusting rates for other potential risk factors such as age.44 Studies of mammary cancer that fail to adjust for neuter status are also subject to bias from confounding.
CANINE AND FELINE CANCER INCIDENCE RATES As described earlier, data for incidence rates of cancer in dogs and cats are limited to a few sources, most of which are badly outdated. The single most important source of incidence data remains the California Animal Neoplasm Registry,2,3 and it is widely referred to when incidence rates are described, despite the fact that the data are more than 40 years old. Table 4-1 provides incidence data for canine and feline cancer obtained from several publications as well as incidence data for human cancer in Alameda County for the same time period.45 These data should be used as approximations of the true incidence of cancer in the 21st century since the caveats provided earlier regarding changes in diagnostic practices, breed distributions, neutering patterns, and animal longevity preclude using them in a definitive context.
ANALYTIC EPIDEMIOLOGY Analytic epidemiology is used to test hypotheses that various risk factors or exposures are associated with the disease (cancer). The hypotheses tested in analytic studies are often developed from data obtained in descriptive epidemiology. A cause-and-effect relationship is difficult to establish from observational studies and may be best evaluated in an experimental setting where all extraneous variables and confounders are carefully controlled. Since cancer incidence rates are generally low and the latent period is likely to be measured in years, experimental approaches to study cancer causation in dogs and cats
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TABLE 4-1
Annual Crude Incidence Rates of Cancer per 100,000 Population for Humans, Dogs, and Cats, Alameda County, 1960 to 1966
Cancer site
Humans
Dogs
Cats
All sites Skin, nonmelanoma Malignant melanoma Digestive Respiratory Connective tissue Mouth and pharynx Breast Lymphoid tumors Bone Testis
272.1a, b 31.8a, e 8.3c 74.5e 32.9e 2.4e 10.3e 37.3e 13.3e 1.2e 2.6e
381.2c 90.4c 25.0c 25.2e 8.5e 35.8c 20.4c 198.8d 25.0d 7.9c 33.9c
155.8c 34.7c NDc 11.2e 5.0e 17.0c 11.6 25.4d 48.1d 4.9c ND
a
Excludes squamous cell carcinoma of the skin. Data adapted from Dorn.71 c Data adapted from Dorn et al.3 d Data adapted from Dorn.72 e Data adapted from Schneider.45 b
are rarely conducted, although several notable exceptions can be cited, for example, lifetime studies of beagle dogs exposed to radionuclides.46 However, a causal inference may be suggested from epidemiologic studies when the evidence meets several criteria including (1) the exposure precedes the development of the disease (temporality); (2) the association between the exposure and the disease can be explained by a biologically plausible mechanism and data from laboratory animal experiments supporting the association may exist (biological plausibility); (3) the association between exposure and disease is strong as measured by the relative risk or odds ratio (strength); (4) the association between the exposure and disease is relatively specific (specificity); and (5) the association has been demonstrated across a number of studies that may use different study designs and have been conducted in various populations (consistency). Although these criteria and others have been applied to assess “causality” in many situations, shortcomings in applying them rigidly have been identified.44 The two principal study designs that have been used in cancer epidemiology are the case-control study and the cohort study. Generally, specific forms of cancer are too rare to apply a cross-sectional design with screening techniques, unless one is examining a high-risk population. The elements of study design and analysis for case-control and cohort studies are beyond the scope of this chapter but have been described elsewhere
with applications to small animal medicine47,48 and in standard textbooks of epidemiology.44 There are many examples of well-conducted case control studies that have identified new risk factors for canine and feline cancers and other disorders. These include studies of exposures to topical flea and tick products and herbicides and bladder cancer,49,50 consumption of vegetables and decreased risk of bladder cancer,51 exposures to secondhand smoke and canine lung and nasal cancer 52,53 and feline lymphoid cancer,54 sunlight exposure and risk of squamous cell carcinoma in cats,55 and exposures to flea control products and oral squamous cell carcinoma in cats.54 The latter study led to a follow-up investigation that reported overexpression of p53 in response to secondhand smoke exposure in cats with oral squamous cell carcinoma.56 Case-control methods have also been applied to develop new knowledge about potential risk factors for feline hyperthyroidism57 and canine gastric dilatation-volvulus syndrome.58 From the standpoint of veterinary oncology and medicine, these studies, if confirmed by further research, offer exciting potential for intervention to reduce the risk of cancer and other diseases in dogs and cats. Preventive approaches to canine and feline cancer have lagged behind developments in diagnosis and therapy but are critical if the burden of cancer in pet animals is to be reduced. Cohort studies have been conducted less frequently than case-control studies in cancer epidemiology for several reasons. First, cancer is a relatively rare event, requiring large sample sizes to yield adequate numbers of cases of specific cancers to conduct analyses with adequate statistical power. Second, the effort involved in following large numbers of dogs or cats prospectively requires considerable resources. Third, although prospective studies can be conducted over a shorter time frame in animals than in humans, the estimated latent period for cancer in the dog and cat must be included in the follow-up period to evaluate the exposure-response relationship. Finally, attrition, loss to follow-up, and changes in exposure status occur over time and contribute to the difficulty of conducting prospective cohort studies. Cohort studies of cancer and other outcomes in pet animals have usually been designed to test specific hypotheses and used high-risk populations to increase efficiency. Incidence rates and relative risk can be measured directly from cohort studies using dog-years at risk to account for varying periods of observation for individual subjects. The author’s experience with cohort studies illustrates the features of the prospective design and the problems associated with this approach.58a Philadelphia area practitioners followed 938 dogs for up to 5 years to determine the incidence of testicular neoplasia in cryptorchid and normal animals matched for age and breed. The cohort
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Chapter 4 • The Epidemiology and Incidence of Cancer experienced a total of 1785 dog-years of risk. The normal (unexposed) and cryptorchid (exposed) subcohorts were matched for age and breed. At the end of 5 years, 1785 dog-years of risk had been accumulated by cohort members. Ten sertoli cell tumors and six seminomas developed in the 609 cryptorchid dogs, none in the 329 normal dogs. Nearly one third of the total cohort could not be followed to the study end point owing to death from competing causes, emigration, failure to return for examination, change in ownership, or change in exposure status (castration). A more efficient design is the retrospective or historical cohort study. In historical cohort studies, the population is identified from previously collected information and the current status of each animal is determined (vital status, cause of death, cancer diagnosis). Cooley et al. conducted a historical cohort study of rottweiler dogs that were followed over a significant proportion of their lifetime.59 Dog owners completed an extensive questionnaire that identified a cohort of 683 dogs that were alive in 1995. After a mean duration of approximately 8.7 years and 71,004 total months of follow-up for the entire cohort, 86 dogs were identified that had radiographic or histologic evidence of osteosarcoma. Multivariate analysis using COX proportional hazards modeling showed a strong association between gonadectomy before 1 year of age and the development of osteosarcoma that was independent of adult height or body weight. Bone sarcoma risk was dose dependent on gonadal hormone levels estimated by date of castration in male dogs.
ENVIRONMENTAL CANCER EPIDEMIOLOGY AND ANIMAL SENTINELS An animal sentinel system is one in which data on animals exposed to contaminants in the environment are collected and analyzed to identify potential health threats.60 Historically, health effects in animals have served as harbingers of environmentally mediated threats to human health. Deaths of fattened cattle at a London stock show occurred during a severe air pollution episode in the 1850s that caused widespread human mortality. Cats consuming fish contaminated with methylmercury developed signs of neurologic disease termed “dancing cat fever” that preceded the development of human illness at Minimata Bay, Japan. More recently, studies of malformed amphibians have raised concerns regarding human exposure to chemicals that may have endocrine disrupting properties. Animal sentinels for cancer have been identified by epidemiologic studies in dogs and cats.61 Several noteworthy examples of environmental exposures that increase risk
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of cancer in animals have been published and will be reviewed here briefly.
Mesothelioma in Dogs and Exposure to Asbestos In 1983, Glickman et al. described a study of mesothelioma in dogs that remains a classic in its approach and significance.62 Eighteen histopathologically confirmed cases of mesothelioma were identified from a hospital population, and owners of 16 of these dogs were interviewed as well as 32 owners of control dogs to determine the dog’s medical history, lifestyle, diet, and potential exposure to asbestos. Owners of dogs with mesothelioma were more likely than owners of control dogs to have been exposed to asbestos at work or by a hobby of a household member. Higher levels of chrysotile asbestosis fibers were identified in the lungs of 3 dogs with mesothelioma and 1 dog with squamous cell carcinoma of the lung than in lung tissue from control dogs and 2 dogs with broncho-alveolar cell carcinoma. There was also a significant association with the use of flea repellants, some of which may have contained asbestoslike fibers. The findings of this study illustrate the usefulness of epidemiologic research that may identify environmental health hazards for humans who share the environment with their pets.
Lung Cancer, Tonsillar Cancer, and Urban Residence Primary lung cancer is rare in dogs. To explore the hypothesis that these cases might be associated with exposure to air pollutants in urban dogs, Reif et al. conducted a study of respiratory tract cancers in the Philadelphia area and assigned exposure based on ambient levels of total suspended particulates.63 The residence of dogs with lung cancer, nasal cancer, tonsillar cancer, gastrointestinal cancer, and a sample of the entire hospital population was compared. No significant association was noted in patient distribution between urban and rural zones for cancer of the lungs and bronchi or nose and paranasal sinuses. However, a significant urban association was noted for dogs with tonsillar carcinoma, 74% of which resided in the urban zone compared with 61% of the total population and 47% of a control group with gastrointestinal neoplasia. In 1939, an association between carcinoma of the tonsil and “townkept” dogs was noted in London.64 The prevalence of tonsillar carcinoma in London was reported to be 12/10,000,65 and in an earlier study in Philadelphia, 9.1/10,000.66 Conversely, Ragland noted that the prevalence in the hospital population in rural Washington was significantly lower (1/10,000),67 and the 2 dogs from Washington were referred from large,
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industrialized cities. The reported urban excess suggests that this cancer may have a role as a sentinel event that should be pursued to test more refined etiologic hypotheses. Studies suggest that dogs that develop cancer of the lung and nasal sinuses may have been exposed to environmental tobacco smoke.52,53 From a public health perspective, smoking cessation can be recommended as a measure to reduce the incidence of human, as well as canine, respiratory tract cancers.
Bladder Cancer, Industry, and Pesticides There are several lines of evidence that bladder cancer in dogs may be associated with exposures to environmental contaminants and that some of these agents may also be associated with human cancer risk. In both humans and dogs, most bladder cancers are transitional cell carcinomas of the urothelium.61 Bladder cancer may be induced experimentally in dogs by administration of aromatic hydrocarbons, including the aromatic amines such as beta-naphthylamine that were used in the textile industry and associated with increased bladder cancer risk in occupationally exposed persons.68 The induction time for chemically induced bladder cancer in dogs is shorter than that reported for humans, suggesting that dogs may be exceptionally sensitive to the effects of these chemicals. Human bladder cancer has been consistently associated with exposures to chemicals in occupationally exposed persons. Canine bladder cancer may also be caused, in part, by exposure to chemicals in the environment. In a study by Hayes et al.,23 the proportional morbidity ratios for bladder cancer in dogs at 13 veterinary teaching hospitals were significantly correlated with level of industrial activity in the same counties, suggesting environmental exposure to carcinogens. An analysis of mortality from bladder cancer among white men and women in the same counties showed a similar correlation with industrial activity. Therefore, the dog may provide a sentinel for detecting the effects of environmental carcinogens, relatively exempt from confounding influences such as occupation and cigarette smoking. The shorter latency period for canine bladder cancer could lead to early identification of carcinogenic hazards in the general environment.23 A case-control study of pet dogs was conducted to determine if exposure to environmental tobacco smoke, use of chemicals in the home, use of topical insecticides, and obesity were associated with the occurrence of bladder cancer.49 Information was obtained by interview from owners of 59 dogs with bladder cancer and 71 ageand breed-sized matched controls with other diseases. Bladder cancer risk was unrelated to environmental tobacco smoke or to household chemical exposures. However, risk was significantly increased by the use of topical insecticides in shampoos and dips. The risk estimate for flea and tick dips was 1.6 for one to
two applications per year and rose to 3.5 for more than two applications per year. This risk was enhanced among obese or overweight dogs rising to an odds ratio (OR) of 3.5 among male dogs and 27.2 among female dogs with both exposures.49 The findings suggested that obesity may modify the risk for exposure to these chemicals by enhancing their lipophilicity in organic solvent carriers. Flea and tick dip products contain up to 96% inert ingredients including petroleum distillates and solvents such as benzene, toluene, and xylene.61 This work focused attention on the need to consider the inert substances in pesticide formulations as potential risk factors for human bladder cancer, especially among nonoccupationally exposed, nonsmoking females.61 The investigators conducted several follow-up studies to evaluate the hypothesis that pesticides are associated with canine bladder cancer risk. The study design was based on case-control analyses of Scottish terrier dogs with bladder cancer and a group of adult Scottish terriers with other disorders recruited through the Scottish Terrier Club of America. Scottish terrier dogs have approximately 18 times the risk of bladder cancer compared to mixed-breed dogs;69 other terrier breeds such as Wirehaired fox terriers and West Highland white terriers are also at increased risk, suggesting a genetic predisposition. In Scottish terriers, treatment with topical spot-on flea and tick products containing fipronil or imidacloprid within 1 year prior to diagnosis was not associated with an increased risk of bladder cancer after adjustment for host factors.70 However, in a study of herbicide exposures, the risk of transitional cell carcinoma was significantly increased among dogs exposed to lawns or gardens treated with both herbicides or insecticides (OR 7.2) or with herbicides alone (OR 3.6) but not among dogs exposed to lawns or gardens treated with insecticides alone.50 Phenoxy acid herbicide exposure was associated with a fourfold increase in risk for bladder cancer in Scottish terriers. Further epidemiological studies of household dogs are needed to identify specific bladder carcinogens in herbicide and insecticide products that are used on animals or in the environment and to assess the potential adverse effects in humans.50 The Scottish terrier model provides an excellent opportunity to test gene-environment interactions in bladder cancer. Studies of gene-environment interactions will constitute the next important phase of cancer epidemiology in pet animals. REFERENCES 1. American Veterinary Medical Association: Results of the AVMA survey on companion animal ownership in US pet-owning households, J Am Vet Med Assoc 221:1572, 2001. 2. Dorn CR, Taylor DON, Frye FL et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. I. Methodology and description of cases, J Natl Cancer Inst 40:295-305, 1968.
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Chapter 4 • The Epidemiology and Incidence of Cancer 3. Dorn CR, Taylor DON, Schneider R et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County, J Natl Cancer Inst 40:307-318, 1968. 4. MacVean DW, Monlux AW, Anderson PS et al: Frequency of canine and feline tumors in a defined population, Vet Pathol 15:700-715, 1978. 5. Bonnett BN, Egenvall A, Olson P et al: Mortality in insure Swedish dogs: rates and causes of death in various breeds, Vet Rec 141:40-44, 1997. 6. Egenvall A, Bonnett BN, Olson P et al: Gender, age and breed pattern of diagnoses for veterinary care in insured dogs in Sweden during 1996, Vet Rec 146:551-557, 2000. 7. Egenvall A, Bonnett BN, Olson P et al A: Gender, age, breed and distribution of morbidity and mortality in insured dogs in Sweden during 1995 and 1996, Vet Rec 146:519-525, 2000. 8. Egenvall A, Bonnett BN, Ohagen P et al: Incidence of and survival after mammary tumors in a population of over 80,000 insured female dogs in Sweden from 1995 to 2002, Prev Vet Med 69:109-127, 2005. 9. Peterson MR, Frommelt RA, Dunn DG: A study of the lifetime occurrence of neoplasia and breed differences in a cohort of German shepherd dogs and Belgian malinois military working dogs that died in 1992, J Vet Intern Med 14:140-145, 2000. 10. Moore GE, Burkman KD, Carter MN et al: Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993–1996), J Am Vet Med Assoc 219:209-214, 2001.
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26. Priester WA: Data from eleven United States and Canadian colleges of veterinary medicine on pancreatic carcinoma in domestic animals, Cancer Res 34:1372-1375, 1974. 27. Hayes HM Jr, Praumernia JF Jr: Canine thyroid neoplasms: epidemiologic features, J Natl Cancer Inst 54:931-934, 1975. 28. Hayes HM, Priester WA, Pendergrass TW: Occurrence of nervous-tissue tumors in cattle, horses, cats and dogs, Int J Cancer 15:39-47, 1975. 29. Dorn CR, Priester WA: Epidemiologic analysis of oral and pharyngeal cancer in dogs, cats, horses, and cattle, J Am Vet Med Assoc 169:1202-1206, 1976. 30. Hayes H: Canine bladder cancer: Epidemiologic features, Am J Epidemiol 104:673-677, 1976. 31. Hayes HM Jr, Pendergrass TW: Canine testicular tumors: epidemiologic features of 410 dogs, Int J Cancer 18:482-487, 1976. 32. Madewell BR, Priester WA, Gillette EL et al: Neoplasms of the nasal passages and paranasal sinuses in domesticated animals as reported by 13 veterinary colleges, Am J Vet Res 37: 851-856, 1976. 33. Hayes HM Jr, Fraumeni JF Jr: Epidemiological features of canine renal neoplasms, Cancer Res 37:2553-2556, 1977. 34. Hayes HM Jr, Young JL: Epidemiologic features of canine ovarian neoplasms, Gynecol Oncol 6:348-353, 1978. 35. Hayes HM Jr, Milne KL, Mandell CP: Epidemiological features of feline mammary carcinomas, Vet Rec 108:476-479, 1981.
11. Cotchin E: Neoplasia in the dog, Vet Rec 66:879-885, 1954.
36. Proschowsky HF, Rugbjerg H, Ersboll AK: Morbidity of purebred dogs in Denmark, Prev Vet Med 58:53-62, 2003.
12. Krook LA: A statistical investigation of carcinoma in the dog, Acta Pathol Microbiol Scand 35:407-422, 1954.
37. Proschowsky HF, Rugbjerg H, Ersboll AK: Mortality of purebred and mixed-breed dogs in Denmark, Prev Vet Med 58:63-74, 2003.
13. Howard EB, Nielsen SE: Neoplasia of the boxer dog, Am J Vet Res 26:1121-1131, 1965.
38. Moore PF: Systemic histiocytosis of Bernese mountain dogs, Vet Pathol 21:554, 1984.
14. Dorn CR, Taylor DON, Chaulk L et al. The prevalence of spontaneous tumors in a defined canine population, Amer J Publ Health 56:254-265, 1966.
39. Bronson RT: Variation in age at death of dogs of different sexes and breeds, Am J Vet Res 43:2057-2059, 1982.
15. Cohen D, Reif JS, Brodey RS: Epidemiological analysis of the most prevalent sites and types of canine neoplasia observed in a veterinary hospital, Cancer Research 34:2859-2868, 1974. 16. Priester WA, Mantel N: Occurrence of tumors in domestic animals: data from 12 United States colleges of veterinary medicine, J Natl Cancer Inst 47:1333-1344, 1971. 17. Bernese Mountain Dog Club of America: BMDCA 2000 Health Survey, www.bmdca.org/health/health_report.htm. 18. Golden Retriever Foundation: National Health Survey, 1998–1999, www.goldenretrieverfoundation.org/insidepagesdata/ healthsurvey/GRCA%20Health%20Survey.pdf. 19. Morris Animal Foundation: Animal health survey, fiscal year 1998. Englewood, CO, 1998, Morris Animal Foundation. 20. Cohen D, Booth S, Sussman O: An epidemiological study of canine lymphoma and its public health significance, Am J Vet Res 20:1026-1031, 1959. 21. Priester WA: Canine lymphoma: Relative risk in the boxer breed, J Natl Cancer Inst 39:833-845, 1967. 22. Dorn CR: Taylor DON, Hibbard HH. Epizootiologic characteristics of canine and feline malignant lymphoma, Am J Vet Res 28:9931001, 1967. 23. Hayes HM Jr, Hoover R, Tarone RE: Bladder cancer in pet dogs: a sentinel for environmental cancer? Am J Epidemiol 114: 229-233, 1981.
40. Craig LE: Cause of death in dogs according to breed: a necropsy survey of five breeds, J Am Anim Hosp Assoc 37:438-443, 2001. 41. Gobar GM, Case JT, Kass PH: Program for surveillance of causes of death of dogs, using the Internet to survey small animal veterinarians, J Am Vet Med Assoc 252-256, 1998. 42. Gobar GM, Kass PH: World Wide Web-based survey of vaccination practices, postvaccinal reactions and vaccine site-associated sarcomas in cats, J Am Vet Med Assoc 220: 1477-1482, 2002. 43. Glickman LT, Moore GE, Glickman NW et al: Purdue University-Banfield National Companion Animal Surveillance Program for emerging and zoonotic diseases, Vector Borne Zoonotic Dis 1:14-23, 2006. 44. Rothman KJ: Epidemiology: an introduction, Oxford, 2002, Oxford University Press. 45. Schneider R: A population based animal tumor registry. In Ingram GD, Mitchell WR, Martin SW, editors: Animal disease monitoring, Springfield, Illinois, 1975, Charles C. Thomas. 46. Benjamin S et al: Occurrence of hemagiosarcoma in beagles with internally deposited radionuclides, Cancer Res 35: 1745-1755, 1975. 47. Reif JS: Ecologic factors and disease. In Ettinger SJ, editor: Textbook of veterinary internal medicine: diseases of the dog and cat, Philadelphia, 1983, Saunders.
24. Tjalma RA: Canine bone sarcoma: estimation of relative risk as a function of body size, J Natl Cancer Inst 36:1137-1150, 1966.
48. Reif JS, Schweitzer DJ, Ferguson SW et al: Canine neoplasia and exposure to uranium mill tailings in Mesa County, Colorado. In Epidemiology applied to health physics; Proc 16th midyear topical meeting, Health Physics Soc, 1983.
25. Priester WA: Skin tumors in domestic animals: data from 12 United States and Canadian colleges of veterinary medicine, J Natl Cancer Inst 50:457-466, 1973.
49. Glickman LT, McKee LJ, Shofer FS et al: Epidemiologic study of insecticide exposures, obesity, and risk of bladder cancer in household dogs, J Toxicol Environ Health 28:407-414, 1989.
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50. Glickman LT, Raghavan M, Knapp DW et al: Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers, J Am Vet Med Assoc 224:1290-1297, 2004. 51. Raghaven M, Knaap D, Bonney PL et al: Evaluation of the effect of dietary vegetable consumption on reducing risk of transitional cell carcinoma of the urinary bladder in Scottish terriers, J Am Vet Med Assoc 277:94-100, 2005.
60. National Research Council: Animals as sentinels of environmental hazards, Washington, DC, 1991, National Academy Press. 61. Kelsey JL, Moore AS, Glickman LT: Epidemiologic studies of risk factors for cancer in pet dogs, Epidemiol Rev 20:204-217, 1998. 62. Glickman L, Domanski L, Maguire T et al: Mesothelioma in pet dogs associated with exposure of their owners to asbestos, Environ Res 32:305-313, 1983.
52. Reif JS, Dunn K, Ogilvie GK et al: Passive smoking and canine lung cancer risk, Am J Epidemiol 135:324-329, 1992.
63. Reif JS, Cohen D: The environmental distribution of canine respiratory tract neoplasms, Arch Environ Health 22:136-140, 1971.
53. Reif JS, Bruns C, Lower KS: Cancer of the nasal cavity and paranasal sinuses and exposure to environmental tobacco smoke in pet dogs, Amer J Epidemiol 147:488-492, 1998.
64. Withers FW: Squamous cell carcinoma of the tonsil in the dog, J Pathol Bact 49:1429-1432, 1939.
54. Bertone E, Snyder LA, Moore ER: Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats, Am J Epidemiol 156:268-273, 2002. 55. Dorn CR, Taylor DON, Schneider R: Sunlight exposure and risk of developing cutaneous and oral squamous cell carcinomas in white cats, J Natl Cancer Inst 46:1073-1078, 1971. 56. Snyder LA, Bertone ER, Jakowski RM et al: p 53 expression and environmental tobacco smoke exposure in feline oral squamous cell carcinoma, Vet Pathol 41:209-214, 2004. 57. Edinboro CH, Scott-Moncrieff JC, Janovitz E et al: Epidemiologic study of relationships between consumption of commercial canned food and risk of hyperthyroidism in cats, J Am Vet Med Assoc 224:879-886, 2004. 58. Raghavan M, Glickman N, McCabe G et al: Diet-related risk factors for gastric dilatation-volvulus in dogs of high-risk breeds, J Am Anim Hosp Assoc 40:192-203, 2004. 58a. Reif JS, Maguire TG, Kenney RM et al: A cohort study of canine testicular neoplasia, JAVMA 175:719-723, 1979. 59. Cooley DM, Beranek BC, Schlittler DL et al: Endogenous gonadal hormone exposure and bone sarcoma risk, Cancer Epidemiol Biomarkers Prev 11:1434-1440, 2002.
65. Cotchin E: Some tumors of dogs and cats of comparative veterinary interest, Vet Rec 71:1040-1054, 1959. 66. Cohen D, Brodey RS, Chen SM: Epidemiologic aspects of oral and pharyngeal neoplasms in the dog, Am J Vet Res 25: 1776-1779, 1964. 67. Ragland WL, Gorham JH: Tonsillar carcinoma in rural dogs, Nature 214:925-926, 1967. 68. Heuper WC, Wiley FH, Wolfe HD: Experimental production of bladder tumors in dogs by administration of beta-naphthylamine, J Industr Hyg Toxicol 20:46-84, 1938. 69. Knapp DW, Glickman NW, DeNicola DB et al: Naturally occurring canine transitional cell carcinoma of the urinary bladder: a relevant model of human invasive bladder cancer, Urol Oncol 5:47-59, 2000. 70. Raghavan M, Knapp DW, Dawson MH et al: Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers, J Am Vet Med Assoc 225:389394, 2004. 71. Dorn CR: The epidemiology of cancer in animals, California Med 107:481-489, 1967. 72. Dorn CR: Epidemiology of canine and feline tumors, Compend Contin Educ Pract Vet 12:307-312, 1976.
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CHAPTER
4
The Epidemiology and Incidence of Cancer John S. Reif
T
here is good evidence to support the statement that cancer is an important disease of dogs and cats at all ages and the leading cause of death in older pet animals. However, developing precise estimates of cancer morbidity and mortality rates in pet animals has been difficult to achieve. When compared to human cancer epidemiology, conducting epidemiologic studies of cancer in dogs and cats is limited by three key data gaps. First, the lack of a census for pet animals precludes measuring morbidity and mortality rates directly, since the population from which the cases originate is generally unknown. In 2001, there were an estimated 73.9 million dogs and 90.5 million cats living in all households in the United States.1 Over 63% of all households reported owning at least one pet during 2005. Eighty-five percent of dogowning households reported taking their dog to a veterinarian in that year, with an average of 1.8 visits per dog. Second, case ascertainment is incomplete and subject to various forms of bias. Since the diagnosis of cancer may require special procedures and diagnostic tests including radiography, ultrasound, and biopsy, not all cases of cancer that are presented to veterinary practices are diagnosed equally. Further, because of the relatively high costs for many advanced diagnostic procedures and treatments, some owners may elect to euthanize pets, especially older animals, without a biopsy or a definitive diagnosis. Third, since death certificates are not required, estimation of mortality has been restricted to relatively few studies where suitable population denominators existed. Similarly, to calculate incidence rates one needs data about the population from which the cases are drawn. For human epidemiology, the creation of state-based cancer registries with comprehensive, mandatory reporting from physicians, hospitals, and diagnostic laboratories has permitted the calculation of population-based incidence rates using census data in denominators. Cancer registries are an invaluable source of data for measuring risk and for comparing cancer incidence over time and from place to place. Most studies of the epidemiology of cancer in pets have been forced to rely on surrogate data sources to estimate 68
morbidity and mortality rates, since population-based data are not readily available.
DESCRIPTIVE EPIDEMIOLOGY Descriptive epidemiology is the first phase of investigation in which disease is described according to three features: the person or animal affected, time, and place. Descriptive epidemiology is used to generate hypotheses regarding potential associations with a variety of exposures, some of which may lie in the causal pathway to disease. Therefore, descriptive studies are essential for understanding the occurrence of cancer in pet animals and setting the stage for testing hypotheses regarding potential causal factors. Hypothesis testing will be discussed later in this chapter under the heading Analytic Epidemiology. Understanding the risk factors for cancer is critical for developing preventive strategies aimed at reducing the risk of developing cancer. Cancer prevention is at its infancy in veterinary medicine and has had only limited success in human medicine. Screening programs for high-risk individuals in human and veterinary oncology may identify cancer at an early stage when the likelihood of treatment success is highest. Rates of disease are calculated to describe the occurrence of cancer in animal or human populations. Morbidity rates estimate the number of new cases of cancer in the population (incidence rates) or existing cases of cancer in the population (prevalence rates), while mortality rates describe deaths from cancer in the population over a suitable time period.
MORBIDITY RATES Cancer Incidence Rates The incidence rate (sometimes referred to incorrectly as “incidence”) of cancer is measured as the number of new cases of cancer developing in a defined
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Chapter 4 • The Epidemiology and Incidence of Cancer population per unit of time such as 1 year. Age-, sex-, and breed-specific incidence rates provide detailed information about the occurrence of cancer in specific segments of the population and are important elements of descriptive epidemiology. Unfortunately, incidence rates for canine and feline cancer are difficult to measure since population-based registries do not exist. Despite this limitation, several studies have been able to calculate incidence rates for canine and feline cancers.
The Alameda and Contra Costa Counties Animal Neoplasm Registry The most comprehensive effort to estimate cancer incidence rates was conducted in a survey of veterinary practices in Alameda and Contra Costa counties (in California) from 1963 to 1966. Dorn et al. attempted to identify all neoplasms diagnosed by enlisting the cooperation of 65 veterinary practices in the two Bay Area counties and 11 practices in contiguous counties that treated animals from Alameda and Contra Costa counties.2 The investigators encouraged participating veterinarians to submit tissue from all suspected cases of neoplasia in return for a free histologic diagnosis. The denominator was estimated by conducting a survey in a probability sample of households in Alameda County to derive the age, sex, and breed distribution of pets and to determine whether the household had used veterinary services. A denominator of dogs and cats from “veterinary using households” was created for the calculation of incidence rates. An estimated annual incidence rate of 3.8 cases of cancer per 1000 dogs was calculated (381/100,000), indicating that almost 4 dogs per 1000 living in households that used veterinary services have a newly diagnosed case of cancer each year. The incidence rate for all cancer in cats was 155.8/100,000. Although this study is badly outdated and many limitations of the data exist due to incomplete ascertainment associated with the diagnostic practices in use in the 1960s and changes in breed distribution since publication, it remains the seminal study for estimating the incidence of canine and feline cancer.3
The Tulsa Registry of Canine and Feline Neoplasms The Tulsa Registry of Canine and Feline Neoplasms was the second animal tumor registry in the United States.4 Histologically confirmed tumors were included in the numerators for calculations of total incidence rate, for rates for benign and malignant neoplasms, and for specific cancer incidence rates. The population at risk was derived by counting all animals seen at all of the 35 participating animal hospitals during the first 2 registry years to estimate the “veterinary-using” population. Among the 63,504 dogs seen by participating veterinarians during the first year, 715 had one or more tumors for an
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incidence rate of 1126 per 100,000. Among 11,909 cats, 56 had at least one tumor for an incidence of 470 cases per 100,000. Tumors of the skin were the most frequently diagnosed neoplasms, as was the case for the California registry study. Note that these rates are about three times higher than those reported for California, due mainly to differences in the method of estimating the denominator.
Studies of Insured Dogs Several studies of morbidity and mortality in insured dogs in Sweden have been published.5,6,7 Data from these studies are derived from observations on more than 200,000 dogs insured by one Swedish company and are believed to represent approximately one third of all Swedish dogs.5 Approximately 50% of Swedish dogs are insured for veterinary care, and approximately two thirds of these are insured by a single company.6 Dogs were insured for life insurance or for veterinary care. Unfortunately from the standpoint of cancer epidemiology, dogs were only eligible for life insurance initially up to the age of 10 years5 and more recently until age 11.7 Few older dogs are covered for veterinary care. Morbidity rates were based on accessions for veterinary care that exceeded a deductible sum (approximately $100). It is not known to what extent insured dogs represent the total population of dogs. Despite these limitations, this database allowed the investigators to calculate overall morbidity and mortality rates for cancer in dogs as well as age-, sex-, and breed-specific rates. The risk for morbidity due to neoplasia was 2.66% among females, 1.58% among males, and 2.13% overall.7 In one publication, the incidence rate of mammary tumors was determined to be 111 per 10,000 dog-years at risk (DYAR).8 The mortality rate for mammary tumors was six deaths per 10,000 DYAR. High-risk breeds (e.g., English springer spaniel, Doberman pinscher, boxer) were identified from the Swedish insurance data. The rates were not adjusted for neuter status but most female dogs in Sweden are not neutered.8
Studies of Military Working Dogs The population of working dogs maintained by the U.S. Department of Defense has also provided an opportunity to study the lifetime incidence of neoplasia and causes of death.9 Approximately 1700 working dogs make up this cohort, which consists primarily of Belgian shepherd dogs (61.5%) and German shepherd dogs (30.6%).10 Among this population of primarily intact male dogs, the lifetime incidence of neoplasia exceeded 30%, with 10% developing more than one neoplasm. Seminoma of the testicle was the most frequently occurring malignancy.9 Although the data are restricted mainly to two breeds, the extensive medical surveillance and necropsy examination that are applied routinely make this dataset of interest.
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Cancer Prevalence Rates Prevalence is the proportion of existing cases of cancer in a population at a single point in time (point prevalence) or over a period of time such as 1 year (period prevalence). Cancer prevalence has been estimated for canine and feline cancers using several types of populations as the denominator. Prevalence estimates have been based on necropsy series,11,12 diagnostic laboratory accessions,13 examination of dogs from pounds,14 single veterinary teaching hospitals,15 a group of veterinary teaching hospitals16 and surveys of breed club members (Bernese Mountain Dog Club, Golden Retriever Foundation)17,18 and dog owners.19 It is critical to consider the population denominator from which the cases of cancer were identified in order to understand the strengths and limitations of the data. None of the populations described is population-based. The denominators used do not represent the population of dogs or cats at large; therefore, estimates of prevalence obtained from these data are subject to selection bias. Nonetheless, usable information can be gleaned from these sources that permit estimation of prevalence adequate to describe general features of the distribution of canine and feline cancer. For example, the high risk of cancer in the boxer dog was first identified in 1959 by examining two case series of malignant lymphoma obtained from 130 participating veterinarians and dog registration data.20 These findings were confirmed in a series of diagnostic laboratory accessions,13 by examining data from the University of Pennsylvania veterinary teaching hospital,15 and with data from the Veterinary Medical Data Program and a series of hospital accessions.21 Boxer dogs were also identified as a high-risk breed for malignant lymphoma in the Alameda and Contra Costa counties animal neoplasm registry.22
The Veterinary Medical Data Base (VMDB) The VMDB was initiated in 1964 by the National Cancer Institute for the purpose of studying cancer in animals. The program was based on collecting standardized abstracts of descriptive, diagnostic, and surgical data from the records of animals seen at participating North American veterinary teaching hospitals. The program began with the recruitment of 11 hospitals and now includes 26 universities that have collectively submitted more than 7 million records to this database. Data from the VMDB have been used for numerous descriptive and analytical epidemiological studies. These investigations have been limited by the small number of potential risk factors included on the abstract but have been useful for identifying risks for numerous types of cancer associated with age, sex, breed, and neutering status. The data have been used rarely to examine geographic differences in cancer prevalence.23 Lack of data for diet, residential history, and specific environmental exposures has
precluded the exploration of specific etiologic hypotheses. However, an extensive series of papers published with VMDB data has permitted the characterization of cancer risk by age, sex, and breed for many canine and feline cancers including tumors of the bone,24 lymphatic system,21 skin,25 pancreas,26 nervous system,28 thyroid,27 mouth and pharynx,29 bladder,30 testicle,31 nasal cavity and paranasal sinuses,32 kidney,33 ovary,34 and mammary gland.35 Despite changes in the distribution of specific breeds of dogs and cats, neutering practices, and longevity over time, data from these studies remain the basis of our understanding of the descriptive epidemiology of many canine and feline tumors. The fundamental weakness in these data is their hospital-based nature and the potential for the introduction of selection bias from nonrepresentative numerator and denominator data.
Survey Data Several surveys of animal owners have been published that provide a crude estimate of the prevalence of various disorders and causes of death. Danish investigators queried members of the Danish Kennel Club in 1997 and received information for 4295 dogs.36 The kennel club represents approximately 53% of all registered dogs in Denmark where registration is compulsory. Tumors accounted for 4.4% of all reported diseases. Higher breedspecific prevalence rates of neoplasia were reported for the English springer spaniel, Hovawart, Samoyed, flatcoated retriever, golden retriever, and beagle, but specific causes of neoplasia were not identified. These authors also described owner-reported causes of mortality for 2928 dogs from the same source population.37 The proportionate cancer mortality was 14.5% (cancer deaths divided by all causes of death). High prevalence of death due to cancer was reported for the Bernese mountain dog, flatcoated retriever, and beagle. Since the data from these studies are self-reported and not confirmed by medical record validation, they are of limited usefulness, despite having a population-based origin. In the United States, several surveys of breed club members have been undertaken. The Golden Retriever Club of America conducted a national health survey of its membership in 1998 and described the findings for more than 1440 dogs.18 The lifetime risk of a golden retriever developing a neoplasm was 50%. Hemangiosarcoma was the most frequently reported cancer with a lifetime risk of 1 in 5, followed by malignant lymphoma with a lifetime risk of 1 in 8. This study separated diagnoses confirmed by a veterinarian from those reported by the owner only. Members of the Bernese Mountain Dog Club confirmed the importance of cancer in this breed in a survey.17 Cancer deaths represented 49% of 261 deaths. Malignant histiocytosis was the most frequent type of cancer in this breed, confirming earlier published reports.38 Finally, Mark Morris Associates conducted an animal health survey in 1998 by mail-back questionnaire
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Chapter 4 • The Epidemiology and Incidence of Cancer in its newsletter. Despite a poor response rate (2.7%), 2003 responses were received. Cancer was listed as the leading cause of death among dogs (47%) and cats (32%).19
MORTALITY RATES Cancer Proportional Mortality Rates Mortality from cancer in dogs and cats has been reported infrequently. The most common source of mortality data is the cancer proportional mortality rate (CPMR). In calculating the CPMR, the number of animals that died from cancer is divided by the number dying of all causes. Typically such data are found in series of necropsied cases. The main shortcoming from such analyses is that the proportion depends not only on the frequency of cancer as a cause of death but on the frequency of all other disorders in the database. Proportionate mortality analyses are prone to selection bias due to the patterns of referral of the institution, the probability that a necropsy will be performed, special interests of the staff, and so on. Many early descriptions of cancer in pet animals were based on series of necropsy examinations and used to infer data for incidence rates with obvious limitations.11,12 A study of 2002 dogs necropsied at the Angell Memorial Animal Hospital found that cancer accounted for 20% of the deaths at 5 years and increased to over 40% in dogs 10 years of age and older, thus supporting the contention that cancer is the leading cause of death among older dogs.39 Another study assessed the CPMR among 1206 golden retrievers, boxers, German shepherd dogs, Labrador retrievers and rottweilers.40 The CPMRs for golden retrievers and boxers were significantly higher than those for the other breeds. The highest CPMR was found for golden retrievers (56.6%), followed by the boxer (51.9%), and German shepherd dog (36.7%). The lowest CPMR was for the rottweiler (28.2%). These data illustrate the importance of cancer as a cause of death even among lower-risk breeds. The age at death was not significantly different among the five breeds, reducing the possibility that confounding by age played an important role in the findings. Ideally, mortality data should be obtained from longitudinal, prospective studies of dog populations or representative samples of these populations. As cohort studies become more commonplace in pet animals, valid mortality data may become available. One potential source of such data is a national database representative of dogs examined by small animal veterinarians and reported systematically by electronic communication.41 The potential usefulness of such a system has been validated by a study assessing the frequency of postvaccinal reactions and vaccine site-associated sarcomas in cats.42 Data from large populations of dogs identified through
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a national surveillance system represent an additional potential source of mortality data.43 Finally, clinical descriptions of death rates among dogs with cancer (dogs dieing of cancer/dogs with cancer) are often referred to as “mortality” rates. These rates are more properly referred to as “case fatality rates” but the usage has become widely accepted.
Adjusted Rates When rates are compared between breeds, sexes, neuter status, geographic location, and other factors, it is important to consider the possibility that confounding may be responsible for observed differences. The risk of most cancers is related to age. Therefore, differences in the age distribution between groups of dogs may introduce bias due to confounding. Standard methods exist for adjusting rates for other potential risk factors such as age.44 Studies of mammary cancer that fail to adjust for neuter status are also subject to bias from confounding.
CANINE AND FELINE CANCER INCIDENCE RATES As described earlier, data for incidence rates of cancer in dogs and cats are limited to a few sources, most of which are badly outdated. The single most important source of incidence data remains the California Animal Neoplasm Registry,2,3 and it is widely referred to when incidence rates are described, despite the fact that the data are more than 40 years old. Table 4-1 provides incidence data for canine and feline cancer obtained from several publications as well as incidence data for human cancer in Alameda County for the same time period.45 These data should be used as approximations of the true incidence of cancer in the 21st century since the caveats provided earlier regarding changes in diagnostic practices, breed distributions, neutering patterns, and animal longevity preclude using them in a definitive context.
ANALYTIC EPIDEMIOLOGY Analytic epidemiology is used to test hypotheses that various risk factors or exposures are associated with the disease (cancer). The hypotheses tested in analytic studies are often developed from data obtained in descriptive epidemiology. A cause-and-effect relationship is difficult to establish from observational studies and may be best evaluated in an experimental setting where all extraneous variables and confounders are carefully controlled. Since cancer incidence rates are generally low and the latent period is likely to be measured in years, experimental approaches to study cancer causation in dogs and cats
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TABLE 4-1
Annual Crude Incidence Rates of Cancer per 100,000 Population for Humans, Dogs, and Cats, Alameda County, 1960 to 1966
Cancer site
Humans
Dogs
Cats
All sites Skin, nonmelanoma Malignant melanoma Digestive Respiratory Connective tissue Mouth and pharynx Breast Lymphoid tumors Bone Testis
272.1a, b 31.8a, e 8.3c 74.5e 32.9e 2.4e 10.3e 37.3e 13.3e 1.2e 2.6e
381.2c 90.4c 25.0c 25.2e 8.5e 35.8c 20.4c 198.8d 25.0d 7.9c 33.9c
155.8c 34.7c NDc 11.2e 5.0e 17.0c 11.6 25.4d 48.1d 4.9c ND
a
Excludes squamous cell carcinoma of the skin. Data adapted from Dorn.71 c Data adapted from Dorn et al.3 d Data adapted from Dorn.72 e Data adapted from Schneider.45 b
are rarely conducted, although several notable exceptions can be cited, for example, lifetime studies of beagle dogs exposed to radionuclides.46 However, a causal inference may be suggested from epidemiologic studies when the evidence meets several criteria including (1) the exposure precedes the development of the disease (temporality); (2) the association between the exposure and the disease can be explained by a biologically plausible mechanism and data from laboratory animal experiments supporting the association may exist (biological plausibility); (3) the association between exposure and disease is strong as measured by the relative risk or odds ratio (strength); (4) the association between the exposure and disease is relatively specific (specificity); and (5) the association has been demonstrated across a number of studies that may use different study designs and have been conducted in various populations (consistency). Although these criteria and others have been applied to assess “causality” in many situations, shortcomings in applying them rigidly have been identified.44 The two principal study designs that have been used in cancer epidemiology are the case-control study and the cohort study. Generally, specific forms of cancer are too rare to apply a cross-sectional design with screening techniques, unless one is examining a high-risk population. The elements of study design and analysis for case-control and cohort studies are beyond the scope of this chapter but have been described elsewhere
with applications to small animal medicine47,48 and in standard textbooks of epidemiology.44 There are many examples of well-conducted case control studies that have identified new risk factors for canine and feline cancers and other disorders. These include studies of exposures to topical flea and tick products and herbicides and bladder cancer,49,50 consumption of vegetables and decreased risk of bladder cancer,51 exposures to secondhand smoke and canine lung and nasal cancer 52,53 and feline lymphoid cancer,54 sunlight exposure and risk of squamous cell carcinoma in cats,55 and exposures to flea control products and oral squamous cell carcinoma in cats.54 The latter study led to a follow-up investigation that reported overexpression of p53 in response to secondhand smoke exposure in cats with oral squamous cell carcinoma.56 Case-control methods have also been applied to develop new knowledge about potential risk factors for feline hyperthyroidism57 and canine gastric dilatation-volvulus syndrome.58 From the standpoint of veterinary oncology and medicine, these studies, if confirmed by further research, offer exciting potential for intervention to reduce the risk of cancer and other diseases in dogs and cats. Preventive approaches to canine and feline cancer have lagged behind developments in diagnosis and therapy but are critical if the burden of cancer in pet animals is to be reduced. Cohort studies have been conducted less frequently than case-control studies in cancer epidemiology for several reasons. First, cancer is a relatively rare event, requiring large sample sizes to yield adequate numbers of cases of specific cancers to conduct analyses with adequate statistical power. Second, the effort involved in following large numbers of dogs or cats prospectively requires considerable resources. Third, although prospective studies can be conducted over a shorter time frame in animals than in humans, the estimated latent period for cancer in the dog and cat must be included in the follow-up period to evaluate the exposure-response relationship. Finally, attrition, loss to follow-up, and changes in exposure status occur over time and contribute to the difficulty of conducting prospective cohort studies. Cohort studies of cancer and other outcomes in pet animals have usually been designed to test specific hypotheses and used high-risk populations to increase efficiency. Incidence rates and relative risk can be measured directly from cohort studies using dog-years at risk to account for varying periods of observation for individual subjects. The author’s experience with cohort studies illustrates the features of the prospective design and the problems associated with this approach.58a Philadelphia area practitioners followed 938 dogs for up to 5 years to determine the incidence of testicular neoplasia in cryptorchid and normal animals matched for age and breed. The cohort
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Chapter 4 • The Epidemiology and Incidence of Cancer experienced a total of 1785 dog-years of risk. The normal (unexposed) and cryptorchid (exposed) subcohorts were matched for age and breed. At the end of 5 years, 1785 dog-years of risk had been accumulated by cohort members. Ten sertoli cell tumors and six seminomas developed in the 609 cryptorchid dogs, none in the 329 normal dogs. Nearly one third of the total cohort could not be followed to the study end point owing to death from competing causes, emigration, failure to return for examination, change in ownership, or change in exposure status (castration). A more efficient design is the retrospective or historical cohort study. In historical cohort studies, the population is identified from previously collected information and the current status of each animal is determined (vital status, cause of death, cancer diagnosis). Cooley et al. conducted a historical cohort study of rottweiler dogs that were followed over a significant proportion of their lifetime.59 Dog owners completed an extensive questionnaire that identified a cohort of 683 dogs that were alive in 1995. After a mean duration of approximately 8.7 years and 71,004 total months of follow-up for the entire cohort, 86 dogs were identified that had radiographic or histologic evidence of osteosarcoma. Multivariate analysis using COX proportional hazards modeling showed a strong association between gonadectomy before 1 year of age and the development of osteosarcoma that was independent of adult height or body weight. Bone sarcoma risk was dose dependent on gonadal hormone levels estimated by date of castration in male dogs.
ENVIRONMENTAL CANCER EPIDEMIOLOGY AND ANIMAL SENTINELS An animal sentinel system is one in which data on animals exposed to contaminants in the environment are collected and analyzed to identify potential health threats.60 Historically, health effects in animals have served as harbingers of environmentally mediated threats to human health. Deaths of fattened cattle at a London stock show occurred during a severe air pollution episode in the 1850s that caused widespread human mortality. Cats consuming fish contaminated with methylmercury developed signs of neurologic disease termed “dancing cat fever” that preceded the development of human illness at Minimata Bay, Japan. More recently, studies of malformed amphibians have raised concerns regarding human exposure to chemicals that may have endocrine disrupting properties. Animal sentinels for cancer have been identified by epidemiologic studies in dogs and cats.61 Several noteworthy examples of environmental exposures that increase risk
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of cancer in animals have been published and will be reviewed here briefly.
Mesothelioma in Dogs and Exposure to Asbestos In 1983, Glickman et al. described a study of mesothelioma in dogs that remains a classic in its approach and significance.62 Eighteen histopathologically confirmed cases of mesothelioma were identified from a hospital population, and owners of 16 of these dogs were interviewed as well as 32 owners of control dogs to determine the dog’s medical history, lifestyle, diet, and potential exposure to asbestos. Owners of dogs with mesothelioma were more likely than owners of control dogs to have been exposed to asbestos at work or by a hobby of a household member. Higher levels of chrysotile asbestosis fibers were identified in the lungs of 3 dogs with mesothelioma and 1 dog with squamous cell carcinoma of the lung than in lung tissue from control dogs and 2 dogs with broncho-alveolar cell carcinoma. There was also a significant association with the use of flea repellants, some of which may have contained asbestoslike fibers. The findings of this study illustrate the usefulness of epidemiologic research that may identify environmental health hazards for humans who share the environment with their pets.
Lung Cancer, Tonsillar Cancer, and Urban Residence Primary lung cancer is rare in dogs. To explore the hypothesis that these cases might be associated with exposure to air pollutants in urban dogs, Reif et al. conducted a study of respiratory tract cancers in the Philadelphia area and assigned exposure based on ambient levels of total suspended particulates.63 The residence of dogs with lung cancer, nasal cancer, tonsillar cancer, gastrointestinal cancer, and a sample of the entire hospital population was compared. No significant association was noted in patient distribution between urban and rural zones for cancer of the lungs and bronchi or nose and paranasal sinuses. However, a significant urban association was noted for dogs with tonsillar carcinoma, 74% of which resided in the urban zone compared with 61% of the total population and 47% of a control group with gastrointestinal neoplasia. In 1939, an association between carcinoma of the tonsil and “townkept” dogs was noted in London.64 The prevalence of tonsillar carcinoma in London was reported to be 12/10,000,65 and in an earlier study in Philadelphia, 9.1/10,000.66 Conversely, Ragland noted that the prevalence in the hospital population in rural Washington was significantly lower (1/10,000),67 and the 2 dogs from Washington were referred from large,
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industrialized cities. The reported urban excess suggests that this cancer may have a role as a sentinel event that should be pursued to test more refined etiologic hypotheses. Studies suggest that dogs that develop cancer of the lung and nasal sinuses may have been exposed to environmental tobacco smoke.52,53 From a public health perspective, smoking cessation can be recommended as a measure to reduce the incidence of human, as well as canine, respiratory tract cancers.
Bladder Cancer, Industry, and Pesticides There are several lines of evidence that bladder cancer in dogs may be associated with exposures to environmental contaminants and that some of these agents may also be associated with human cancer risk. In both humans and dogs, most bladder cancers are transitional cell carcinomas of the urothelium.61 Bladder cancer may be induced experimentally in dogs by administration of aromatic hydrocarbons, including the aromatic amines such as beta-naphthylamine that were used in the textile industry and associated with increased bladder cancer risk in occupationally exposed persons.68 The induction time for chemically induced bladder cancer in dogs is shorter than that reported for humans, suggesting that dogs may be exceptionally sensitive to the effects of these chemicals. Human bladder cancer has been consistently associated with exposures to chemicals in occupationally exposed persons. Canine bladder cancer may also be caused, in part, by exposure to chemicals in the environment. In a study by Hayes et al.,23 the proportional morbidity ratios for bladder cancer in dogs at 13 veterinary teaching hospitals were significantly correlated with level of industrial activity in the same counties, suggesting environmental exposure to carcinogens. An analysis of mortality from bladder cancer among white men and women in the same counties showed a similar correlation with industrial activity. Therefore, the dog may provide a sentinel for detecting the effects of environmental carcinogens, relatively exempt from confounding influences such as occupation and cigarette smoking. The shorter latency period for canine bladder cancer could lead to early identification of carcinogenic hazards in the general environment.23 A case-control study of pet dogs was conducted to determine if exposure to environmental tobacco smoke, use of chemicals in the home, use of topical insecticides, and obesity were associated with the occurrence of bladder cancer.49 Information was obtained by interview from owners of 59 dogs with bladder cancer and 71 ageand breed-sized matched controls with other diseases. Bladder cancer risk was unrelated to environmental tobacco smoke or to household chemical exposures. However, risk was significantly increased by the use of topical insecticides in shampoos and dips. The risk estimate for flea and tick dips was 1.6 for one to
two applications per year and rose to 3.5 for more than two applications per year. This risk was enhanced among obese or overweight dogs rising to an odds ratio (OR) of 3.5 among male dogs and 27.2 among female dogs with both exposures.49 The findings suggested that obesity may modify the risk for exposure to these chemicals by enhancing their lipophilicity in organic solvent carriers. Flea and tick dip products contain up to 96% inert ingredients including petroleum distillates and solvents such as benzene, toluene, and xylene.61 This work focused attention on the need to consider the inert substances in pesticide formulations as potential risk factors for human bladder cancer, especially among nonoccupationally exposed, nonsmoking females.61 The investigators conducted several follow-up studies to evaluate the hypothesis that pesticides are associated with canine bladder cancer risk. The study design was based on case-control analyses of Scottish terrier dogs with bladder cancer and a group of adult Scottish terriers with other disorders recruited through the Scottish Terrier Club of America. Scottish terrier dogs have approximately 18 times the risk of bladder cancer compared to mixed-breed dogs;69 other terrier breeds such as Wirehaired fox terriers and West Highland white terriers are also at increased risk, suggesting a genetic predisposition. In Scottish terriers, treatment with topical spot-on flea and tick products containing fipronil or imidacloprid within 1 year prior to diagnosis was not associated with an increased risk of bladder cancer after adjustment for host factors.70 However, in a study of herbicide exposures, the risk of transitional cell carcinoma was significantly increased among dogs exposed to lawns or gardens treated with both herbicides or insecticides (OR 7.2) or with herbicides alone (OR 3.6) but not among dogs exposed to lawns or gardens treated with insecticides alone.50 Phenoxy acid herbicide exposure was associated with a fourfold increase in risk for bladder cancer in Scottish terriers. Further epidemiological studies of household dogs are needed to identify specific bladder carcinogens in herbicide and insecticide products that are used on animals or in the environment and to assess the potential adverse effects in humans.50 The Scottish terrier model provides an excellent opportunity to test gene-environment interactions in bladder cancer. Studies of gene-environment interactions will constitute the next important phase of cancer epidemiology in pet animals. REFERENCES 1. American Veterinary Medical Association: Results of the AVMA survey on companion animal ownership in US pet-owning households, J Am Vet Med Assoc 221:1572, 2001. 2. Dorn CR, Taylor DON, Frye FL et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. I. Methodology and description of cases, J Natl Cancer Inst 40:295-305, 1968.
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Chapter 4 • The Epidemiology and Incidence of Cancer 3. Dorn CR, Taylor DON, Schneider R et al: Survey of animal neoplasms in Alameda and Contra Costa Counties, California. II. Cancer morbidity in dogs and cats from Alameda County, J Natl Cancer Inst 40:307-318, 1968. 4. MacVean DW, Monlux AW, Anderson PS et al: Frequency of canine and feline tumors in a defined population, Vet Pathol 15:700-715, 1978. 5. Bonnett BN, Egenvall A, Olson P et al: Mortality in insure Swedish dogs: rates and causes of death in various breeds, Vet Rec 141:40-44, 1997. 6. Egenvall A, Bonnett BN, Olson P et al: Gender, age and breed pattern of diagnoses for veterinary care in insured dogs in Sweden during 1996, Vet Rec 146:551-557, 2000. 7. Egenvall A, Bonnett BN, Olson P et al A: Gender, age, breed and distribution of morbidity and mortality in insured dogs in Sweden during 1995 and 1996, Vet Rec 146:519-525, 2000. 8. Egenvall A, Bonnett BN, Ohagen P et al: Incidence of and survival after mammary tumors in a population of over 80,000 insured female dogs in Sweden from 1995 to 2002, Prev Vet Med 69:109-127, 2005. 9. Peterson MR, Frommelt RA, Dunn DG: A study of the lifetime occurrence of neoplasia and breed differences in a cohort of German shepherd dogs and Belgian malinois military working dogs that died in 1992, J Vet Intern Med 14:140-145, 2000. 10. Moore GE, Burkman KD, Carter MN et al: Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993–1996), J Am Vet Med Assoc 219:209-214, 2001.
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54. Bertone E, Snyder LA, Moore ER: Environmental and lifestyle risk factors for oral squamous cell carcinoma in domestic cats, Am J Epidemiol 156:268-273, 2002. 55. Dorn CR, Taylor DON, Schneider R: Sunlight exposure and risk of developing cutaneous and oral squamous cell carcinomas in white cats, J Natl Cancer Inst 46:1073-1078, 1971. 56. Snyder LA, Bertone ER, Jakowski RM et al: p 53 expression and environmental tobacco smoke exposure in feline oral squamous cell carcinoma, Vet Pathol 41:209-214, 2004. 57. Edinboro CH, Scott-Moncrieff JC, Janovitz E et al: Epidemiologic study of relationships between consumption of commercial canned food and risk of hyperthyroidism in cats, J Am Vet Med Assoc 224:879-886, 2004. 58. Raghavan M, Glickman N, McCabe G et al: Diet-related risk factors for gastric dilatation-volvulus in dogs of high-risk breeds, J Am Anim Hosp Assoc 40:192-203, 2004. 58a. Reif JS, Maguire TG, Kenney RM et al: A cohort study of canine testicular neoplasia, JAVMA 175:719-723, 1979. 59. Cooley DM, Beranek BC, Schlittler DL et al: Endogenous gonadal hormone exposure and bone sarcoma risk, Cancer Epidemiol Biomarkers Prev 11:1434-1440, 2002.
65. Cotchin E: Some tumors of dogs and cats of comparative veterinary interest, Vet Rec 71:1040-1054, 1959. 66. Cohen D, Brodey RS, Chen SM: Epidemiologic aspects of oral and pharyngeal neoplasms in the dog, Am J Vet Res 25: 1776-1779, 1964. 67. Ragland WL, Gorham JH: Tonsillar carcinoma in rural dogs, Nature 214:925-926, 1967. 68. Heuper WC, Wiley FH, Wolfe HD: Experimental production of bladder tumors in dogs by administration of beta-naphthylamine, J Industr Hyg Toxicol 20:46-84, 1938. 69. Knapp DW, Glickman NW, DeNicola DB et al: Naturally occurring canine transitional cell carcinoma of the urinary bladder: a relevant model of human invasive bladder cancer, Urol Oncol 5:47-59, 2000. 70. Raghavan M, Knapp DW, Dawson MH et al: Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers, J Am Vet Med Assoc 225:389394, 2004. 71. Dorn CR: The epidemiology of cancer in animals, California Med 107:481-489, 1967. 72. Dorn CR: Epidemiology of canine and feline tumors, Compend Contin Educ Pract Vet 12:307-312, 1976.