The comparative epidemiology of selected neoplasms between dogs, cats and humans. A review

Eu~.p. [J. c'ancer Vol. 00, pp. 129~1308. Illll b2964/78/120 I-1299 S02.0O/0 I Pergamml Press Ltd. 1978 Printed in (;rval Britain

Perspectives in Cancer Research

The Comparative Epidemiology of Selected Neoplasms Between Dogs, Cats and Humans. A Review

HOWARD M. HAYES, JR.

Environmental Epidemiology Branch, National Cancer Institute, 3C07 Landow, Bethesda, MD 200t4, U.S.A.

T~IERE are a multitude of factors implicated in the etiology of cancer. Singly or in combination, determinants such as viruses, genetic susceptibility, alterations of endocrine metabolism, and exposures to solar radiation, X- radiation, certain chemicals, radioactive ele- ments, inorganic substances, foods and drugs have been identified [1]. Yet, there is considerably more research to be done. Who is at risk for cancer, when and why? Some of the answers may lie in gaining new knowledge about disease processes in lower animals.

Proof o f the kinship in the etiology of animal and human cancer is easily demo- nstrated by the work of Holsti and Ermala [2]. These investigators attempted to induce lung cancer in mice by painting their oral mucosa with tobacco tar. Rather than pro- ducing tumors of the lung, they induced carcinomas of the urinary bladder• The association of tobacco usage and subsequent bladder cancer in humans has now been established and quantified [3, 4].

The study of spontaneous occurring neoplasms in animals has recently gained further impetus. With the identification of excessive mortality rates of particular human cancers in specific U.S. counties [5], it now makes it possible to pursue the epidemiology of the lesion in similarly exposed pets. Dogs and cats which are.l~el)t as pets could be an ideal sentinel f0r momtormg the effects of low-level environmental contaminants. Pets share their owner's environment except for work-related exposures and tobacco usage. These two con- founding variables presently bias many human surveys.

This review concerns the epidemiology of canine and feline neoplasms of the testis,

1299

ovary, mammary gland, urinary bladder, kidney, thyroid gland, chemoreceptor system, brain and blood-lymphatic system. Comparisons will be drawn between the human and veterinary epidemiology when possible.

TESTIS

The m6rtality rate from testicular neoplasms has doubled in men in the last 20 yr [6]. This lesion is now the leading cause of cancer death in the U.S. among men between the ages of 25 and 29 [5]. These neoplasms are second in hospital prevalence in the dog [7], but are very rare in the cat.

Men and dogs share many of the epidemiologic features of testicular tumors; the primary exception is the different frequency of occurrence of certain cell-types. Embryonal carcinomas and teratomas predominate in children and seminomas in adults, but Sertoli cell and interstitial cell tumors in humans are quite rare [6]. In the dog, seminomas, Sertoli cell tumors, and interstitial cell tumors occur with about equal frequency; teratomas have been unreported [7].

Several canine breeds have been identified with an excessive risk of one or more cell- types of testis including the Boxer, \Vcim~Y~ll,'F. S,l~clland Sheepdog and German Shepherd dog. \Vhat is intriguing is that the factor(s) responsible for the familial risk in Boxers expressed itself in three different tumor cell-types, whereas in the Weimaraner, just two cell-types were present excessively, and in the Shetland Sheepdog and German Shepherd dog only one cell-type [7]. In about half of the infrequent familial aggregates of testicular

1300 ttoward 31. Hq~'e.~, fir.

neoplasia in man, more than one tumor cell- type was exhibited [8].

Other factors besides inheritance must play a large role in testicular tumorigenesis. There is some evidence to suggest that environmental exposures associated with rural or urban living contribute to the origin of seminomas in man [9-12]. Unfortunately, comparative data for dogs are not presently available.

(:ryl)torchism has hmg bccn redognizcd as a contributing factor to tcsticular neoplasia. Whether the etiology of the tumor(s) is foun- ded only upon the dysgenetic gonad or is also the result of the inguinal and intra-abdominal environment is debatable [8]. Cryptorchid dogs have an estimated risk for testis tumors 13.6 times that of normal dogs [7]. In cryptorchid men, the relative risk has been estimated to be 14 bv Mostofi [6] and 8.8 bv Morrison 1131. However. tmnor ccll-t.Vl)eS associated with the deti~ct are ditt~rent in each species. Among cryptorchid men, seminomas are the major cell-type [6, 13], while seminomas and Sertoli cell tumors share about equal risk in cryptorchid dogs [7]. Interstitial cell tumors have not been observed with cryptorchism in humans and only very rarely in dogs.

The Shetland Sheepdog has been proposed as an appropriate canine model for further research into testicular maldescent and tumorigenesis [7]. This breed has a predilection for the occurrence of each independent lactor [7, 14] , plus the concomitant occurrence of both [71.

OVARY

Ovarian malignancies represent 5~o of the cancers diagnosed in U.S. women. Epithelial neoplasms account for about 75",, of the U.S. incidence of ovcrian cancer in xvhitc f;'malcs [15]. Second most frequent are granulosa- theca cell tumors. In the largest canine study yet presented, epithelial neoplasms accounted for 60% and granulosa-theca cell tumors 27~!{~ of the classifiable ovarian tumors [16]. Overall, ovarian neoplasms are infrequently seen in the dog and cat.

Epithelial ovarian cancers, as a group, show consistently increasing incidence with age th- rough 75yr in women. In contrast, the incidence rates for malignant granulosa-theca cell tumors present two relatively static levels of occurrence with 45yr being the age when risk increases [15]. Similarly in dogs, risk increases strikingly with age for bitches with

epithelial ovarian tumors. Those with granulosa-theca cell tumors have a generally constant risk between 4 and 15yr of age, followed by an increase [16].

There is a strong histologic similarity between ovarian neoplasms in dogs and those in women with the exception of granulosa-theca cell tumors. These tumors show considerably more morphological variation in bitch dogs than in women. This finding led Willis [17] to suggest that granulosa-theca cell tumors and epithelial ovarian tumors in the dog may share a common etiology. However, his hypothesis is not consistent with the reported epidemiology of the lesion [ 16].

There is little evidence of a familial association of ovarian neoplasms in women [18]. However, the incidence of ovarian cancer is much higher in white than black women. The difference here is attributed to the much higher incidence of epithelial ovarian cancer in whites over 45yr of age than experienced by blacks [19]. Inheritance plays only a small role, at most, in the etiology of the canine lesion as the Pointer is the only breed identified with high risk for ovarian cancer [16].

The pathogenesis for spontaneous ovarian tumors in humans and animals is obscure. Suspected causes among women include hor- monal imbalances and environmental carcinogens. Lingeman, in her treatise on human ovarian cancer [18], suggests the latter as the most prominent cause of the lesion, although few definitive clues exist. Unfortunately, the presently known epidemiologic features of canine ovarian cancer shed no new light on etiology [16]. Yet, the bitch dog does appear to be a suitable model for testing suspected ovarian carcinogens in women because of the similarities of the disease in both subjects.

M A M M A R Y GLAND

Tumors of the mammary gland are the most common neoplasm in the female dog but are infrequent in the cat [20]. The ratio of female to male dogs wittl the lesion is about 50:1, which is about the same ratio in people 121 ]. The distribution of mammary cancer by age in bitch dogs appears similar to that in women, using Lebeau's [22] dog-years to human-years formula [23].

Histologically, feline mammary carcinomas are more readily recognized as malignant than those from the dog. But occasionally in the cat, and often in the dog, mammary carcinomas are not uniform in histologic ap-

Epidemiology of Neoplasms between Dogs, Cats and Humans 1301

pearance. As in women, it appears that a correlation exists in cats between the histologic grading of malignancy and prognosis [24].

A relationship between tumor risk and pa- rity in the bitch dog has been disputed [23, 25-27]. Schneider et al. [23] have reported a significant sparing effect for mammary cancer occurs in the bitch dog that had an oophorec- tomt prior to 2½yr of age. Studies of human breast cancer show that (1) risk increases with the age of the mother at giving first birth, (2) women under 30 yr of age who complete a full term pregnancy have less cancer risk than nulliparous women, although cancer protec- tion is generally not enhanced by additional births [21], and (3) oophorectomy in women under 40yr of age has a protective effect against the later development of breast cancer [28].

Familial factors do play a role in the etiology of the tumor. Female relatives of women with breast cancer have 2-3 times the risk for the lesion than the general population [21]. The increased risk is especially evident in the patient's children [29, 30].

In dogs, an excessive risk for mammary cancer has been identified in four canine breeds- - Miniature Poodle, English Setter, German Shorthair Pointer and Pointer; it is important to note that the Pointer breed is also at high risk for ovarian cancer [18]. The occurrence of both cancers has been linked in some human families [31].

More investigation is needed to delineate factors possibly affecting canine and feline mammary cancer (i.e., obesity, the precursor effect of benign mammary neoplasms). Yet, there appears to be ample reason to use the dog and cat as models for research.

URINARY BLADDER

In the U.S. bladder cancer accounts for 4.3Uo of the incidence of all malignancies in humans [15]. In dogs, it represents 1°/o of the hospital prevalence of cancer [32], but is much rarer in cats [20]. Transitional cell carcinoma is the most common cell-type diagnosed in people [33] and dogs [32].

Four canine breeds (Scottish Terrier, Shetland Sheepdog, Collie, Beagle) show a marked propensity for the malignancy [32]. There is little evidence for an inheritance role in humans, although two families have been identified with an unusual aggregation of 1)ladder tumors [34, 35]. One characteristic investigated in the living members of these

families was their level of urinary tryphophan metabolites, a suspected cause of bladder cancer [33]. The similarities in the tryphophan metabolism between humans and dogs [36, 37] suggest that further studies using high-risk breeds of dogs could be helpful.

Female dogs have been detected with 1.5 times the risk of male dogs (P<0.05) for the tumor [32]. This sex differential probably occurs because of the infrequent urination, on a daily basis, by the female dog as compared to the male [38]. Urine-borne carcinogenic agents thus would have longer exposure to the bladder epithelium in the female than the male dog.

The sex risk is reversed in humans [15]. About one-tenth of the incidence of bladder cancer in men is reportedly associated with cigarette smoking [4, 39] and occupational exposures to chemicals, e.g., aromatic amines [33].

Recent canine trials indicate a dose-time relationship can also exist in the etiology. The total dose of carcinogen required to produce tumors is considerably less if given in small amounts over an extended period of time [40]. The latent period has been as long as 10yr in some trials. Yet, once carcino- genesis has been initiated, removal of the exposure does not inhibit the growth of the tumor [41]. The overall low frequency of bladder cancer in dogs is consistent with a low dose response to general environmental exposures over an extended period of time [32].

It has been proposed that canine bladder cancer should be made a reportable disease in the U.S. [32]. Increasing case counts over time would possibly identify geographic areas where emerging environmental hazards to humans are now present.

KIDNEY

Very little is known about the etiology of renal carcinoma in animals and man. Wynder [42], in a review about the human lesion, proposed nutritional factors, e.g., animal fats and cholestoral, as a possible cause.

The epidemiology of feline renal carcinoma has been described. However, the recent de- scription of canine renal carcinoma indicates an epidemiology very similar to that in humans [43].

Renal carcinoma accounts for 2c}/o of human cancer in the U.S. [15]. In the dog, the tumor represents slightly less than lUl, of

1302 Howard M. Hayes, ,yr.

diagnosed malignancies. In neither species arc" genetic determinants conspicuous, although both men and male dogs are at increased risk for the lesion [15, 43]. And further, the male risk by age of canine renal carcinoma re- sembles the pattern of risk in men [43].

The reason for the male predominance of human renal carcinoma is obscure. Environmental factors are suggested by the rising incidence among American men, but not. among women [44] and call for further studies into the role of tobacco, nutrition and occupational determinants. However, these factors cannot account for the male excess in dogs (and similar trends in sex ratio with age) and suggest the influence of host susceptibility, including the endogenous production or metabolism of sex hormones. This scenario is consistent with the evidence of remission in some human patients if treated with progesterone [45, 461.

THYROID GLAND

Endocrine malignancies compose 1.4~}~, of all human cancers in the U.S. [15], 3.7 and 0.9% of the diagnosed cancers in dogs and cats [20]. Carcinoma of the thyroid is the predominant lesion among endocrine cancers. An environmental influence, linked with en- demic goiter, has been disputed as an etiologic factor in human beings [47] and dogs [48]. X-radiation, a well-known etiologic agent for the human lesion [49], has not been implicated in the spontaneous neoplasia of the gland in domestic animals [48].

The morbidity and mortality from thyroid cancers is about 2½ times greater in women than in men [15, 47]. Statistically, the diagnos- tic frequency in dogs shows no sex difl~rential [148]. Familial aggregates of medullary thyroid carcinoma, singularly or in combination with other endocrine abnormalities, have been reported in man [50]. In dogs, breed pre- dispositions for thyroid carcinoma have been detected in Boxers, Golden Retrievers and Beagles [48]. However, medullary thyroid carcinoma rarely occurs in dogs [51].

The excess risk among Boxer dogs is thought to be partly due to the anomalous tbllicular patterns commonly seen in their thyroid glands. More interesting may be the finding of excessively high risk among the Beagle breed. Investigators have reported an unexplained high prevalence of thyroiditis in several Beagle colonies used in laboratory research [52, 53]. This type of thyroiditis is indistinguishable from Hashimoto's thyroiditis

in man [54], which may predispose man to thyroid carcinoma [55-58]. Follow-up studies of Beagles with thyroiditis could clarify this relationship.

Certain other primary neoplasms have been identified in humans and dogs as occurring in association with thyroid carcinoma. One is a syndrome called multiple endocrine adenomatosis, type 1, which is a dominantly in- herited constellation of tumors composed of adenomas and carcinomas of several endocrine organs, plus occasionally multiple lipomas [48, 59 61]. Another syndrome is one that involves tumors of the thyroid and chemoreceptor system (chemodectomas) [62-63].

C H E M O R E C E P T O R SYSTEM

The chemoreceptor system consists of nu- merous morphologically similar glomera located throughout the body. In people, the larger clusters of cells have been named the glomus jugulare, glomus pulmonale, aortic body and carotid body.

Although the function and mode of action is not completely understood, the aortic and carotid bodies have been shown to be re- sponsive to changes in the oxygen and carbon dioxide tensions, pH, and temperature of the circulating blood [64]. These bodies can in- itiate an increase in the depth, minute volume and rate of respiration via parasympathetic innervation. Also, via the sympathetic nervous system, they can increase the heart rate and elevate the arterial blood pressure. The human and canine chemoreceptor systems are quite similar.

Chemodectomas are uncommon in humans and dogs and very rarely occur in cats. In people, they occur twice as often in the carotid body than other sites [65]. Conversely, about 80°i~ of the chemodectomas in dogs are located at the aortic body [63]. Chemodectomas, regardless of location however, are histologically indistinguishable. There is usually no correlation between histologic appearance of this tumor and its malignancy potential [66].

The number of human chemodectomas observed in each sex has been about the same with one exception; Peruvians who live in the Andes experience a 6-fold excess among women [65, 67]. In dogs, males have about 2 times the prevalence of females [681. In neither humans nor dogs are the reasons for this sex differential known. However, an asso.ciation of seminomas and interstitial cell tumors in con-

Epiderniology of Neoplasms between Dogs, Cats and Human.; 1303

junction with canine chemodectomas has been reported [63, 69].

Some of the determinants in the etiology of chemodectomas are known. Genetic factors have been implicated, by familial aggre- gations, in about 800 of the lesions in people [67, 70]. Further, chronic hypoxia seems to be implicated, at least among the Peruvians living at high altitudes [65].

In dogs, only breeds of brachycephalic English Bulldog family (i.e., Boxer, Boston Terrier) have been detected with significantly high risk [68]. These breeds frequently have soft tissue anomalies of the oral and nasal cavities which restrict and impede respiration [71, 72]. Yet, other brachycephalic breeds, such as the Pekingese and Pug, show no affinity for chemodectomas. Thus, for Bulldog breeds, a genetic predisposition plus an aggravation of respiratory distress may be necessary factors responsible for the tumorigenesis of their chemoreceptor system [68].

BRAIN

Intracranial neoplasms have held a special interest for researchers over many centuries. Irrespective of the tumor's behavior (benign or malignant), these neoplasms have an in- sidious effect caused by the increase in intracranial pressure due to tissue displacement.

The annual age-adjusted incidence of brain tumors in humans is about 5 per 100,000 in the U.S. [15]. These tumors are rare in domestic animals with the exception of the dog [73]. Gliomas, astrocytomas, and glioblas- tomas are the predominant tumor types of the brain in adult humans and dogs. Medulloblastomas predominate in children. Little is known about the types of brain tumors that occur in puppies.

The age distribution in humans is bi-phasic. The childhood peak is under 10yr of age and the adult peak is 64-69yr [15]. The peak risk in dogs occurs between 10 and 14yr of age [73], the median of which approximates the second peak in humans [22]. White men have more brain tumors than white women, however no sex differential is evident in U.S. blacks [15]. No sex risk has been noted in dogs [73].

The etiology of naturally occuring brain tumors is obscure. An association of reticulum cell sarcoma in the human brain following renal transplant and immunosuppression has been observed [74]. In dogs, gliomas have been induced with Rous sarcoma virus [75].

Familial excesses for astrocytomas have been reported in people [76, 77]. In dogs, only breeds of English Bulldog ancestry show high risk [73]. As mentioned before, this composite dog family commonly have soft tissue anomalies of the nose and mouth which may result in chronic hypoxia.

Chronic hypoxia in humans can be a sti- mulus for fibrillary gliosis in the neonatal and infantile brain [78], the severity of which appears to be correlated with the length of time of prolonged hypoxia [79]. Gliosis may be a precursor of gliomas and other related tumors. Or, the conditions may share a common etiology (i.e., chronic hypoxia), since the entire spectrum of nodular and diffuse gliosis, gliomatosis, astrocytomas, and glioblastoma has been concurrently observed in people [80- 82].

B L O O D - L Y M P H A T I C SYSTEM

Tumors of the hematopoietic system are the most common neoplasms diagnosed in cats and rank fourth in occurrence in dogs. The leukemia-lymphoma complex ranks first in cats and dogs for the percentage of malignancies [20]. Leukemia accounts for about half of the incidence of cancer in children under 5 yr of age. Lymphomas account for about 3~Io of the cancers in the same age group. Each lesion represents 3.25°i) of the annual age-adjusted incidence of cancer in the U.S. [15]. The age distribution of feline lymphosarcoma is bi- phasic [83] and similar in age pattern to human leukemia [ 15].

Lymphoid tumors constitute most of the hematopoietic neoplasms in dogs and cats, and lymphosarcoma is the most common form of malignancy of the system. It should be noted that the term "leukemia" in the veterinary literature has often been used as a general term to represent, in fact, lymphosarcoma. Histologically, lymphosarcoma in the dog and cat are similar and resemble the disease in man.

The Boxer [84-86] and English Pointer [86] have been identified with significantly high risk for canine lymphosarcoma. No sex- specific features are evident in the dog [86]. Unlike feline lymphosarcoma, transmission of the canine disease has been unsuccessful with cell-free distillates of the tumor [87].

Lymphosarcoma is the most prevalent malignant tumor in cats. No breed predisposition has been established. Although, males appear

1304 ttou,ard M. Hayes, j r .

to have a 2-fold risk compared with females [83].

T h e etiology of the feline lesion is a C-type R N A virus [88], commonly referred to as feline leukemia virus (FeLV). FeLV has been t ransmit ted by cat- to-cat contact in the labo- ra tory [89]. This is also the likely mode of transmission in the general popula t ion [90]. T h e er rant and often hostile instincts of the male (non-castra ted) cat to other male cats may subject them to sufficient cat- to-cat contact that could explain their 2-fold risk for Fe LV infection.

Feline lymphosa rcoma has been associated with at least one other infectious disease, feline infectious anemia (FIA). F IA is caused by an infection with Hemobar tone l l a fells, a protozoan, and can result in severe anemia.

Cats with acute clinical expression of FIA have 12 times the risk of deve lopment of feline lymphosa rcoma as matched controls [191]. Th e exact association between FIA and feline lymphosarcoma or between severe anemia and subsequent lymphosarcoma is unclear [92]. As in experiments with rats and mice [93, 94], severe anemia may trigger clinical lymphosarcoma in the cat. However , the causal or- ganisms of F IA and FeLV could, in sore,' way, be linked. Similar to lymphosarcom:l . FIA appears to be natura l ly t ransmit ted by cat- to-cat contact ; male cats have a 2.5 fold risk for acute clinical disease [95].

Evidence has been presented to show F eLV can cross species barriers. Newborn and young puppies inoculated with FeLV will develop lymphosarcoma [96, 97]. O f great impor tance is the fact that F eLV will replicate in h u m a n cells [98, 99]. M a n y studies have evaulated the possibility of ca t - to -human transmission of FeLV; none have shown the FeLV is a hazard to man [100].

C O N C L U S I O N S

Recent da ta about the epidemiologic features of 9 different tumor sites in dogs and cats have been reviewed. Far more infor- mat ion is general ly known about cancer that occurs in dogs than in cats. T h e epidemiologic features tbr canine tumors at most organ sites show marked similarity to those in humans. Although, the f requency of par t icular cell- types at some organs often differs. Th e similarities in risk by age and sex should encourage further research to de termine which cancers in the dog are correlated with envi ronmenta l t'actors that affect h u m an beings. Identif icat ion and moni tor ing the f requency of these canine cancers may provide a prognostic resource about subsequent envi ronmenta l ly in- thlenced cancer in h u m an beings.

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Documents

The comparative epidemiology of selected neoplasms between dogs, cats and humans. A review