Prevalence and Etiology of the Most Common Malignant Tumours in Dogs and Cats

Bulgarian Journal of Veterinary Medicine (2006), 9, N o 2, 85 −98

PREVALENCE AND ETIOLOGY OF THE MOST COMMON MALIGNANT TUMOURS IN DOGS AND CATS

I. TODOROVA

Department of Surgery, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria

Summary

Todorova, I., 2006. Prevalence and etiology of the most common malignant tumours in dogs and cats. Bulg. J. Vet. Med. , 9, No 2, 85 −98.

Cancer is a multistage process with a polyfactorial etiology. Its development results from the effect of various carcinogens such as ionized radiation, chemicals and oncogenic viruses. The impact of many endogenous factors − genetic, immune and hormonal, is also very important. Under the effect of these factors, changes in the DNA of genes often occur. Some dogs probably inherit some of abnormal genes that are precondition for the malignant cell transformation. The risk factors influence either directly or indirectly on tumour suppressor genes and oncogenes. Some DNA (herpes viruses, papova- and adenoviruses) and RNA viruses (retroviruses) are named tumour viruses as they are proved to cause cancer in infected cells. Unlike viral infections that are related only to some of neoplastic diseases, chemical carcinogens play a role in the development of most forms fo cancer. Food contains natural chemicals that could also lead to DNA damage and pro- duce cell alterations. The oncogenic effect of ionized radiation, depending on the dose, type of radiation and the way it was released is beyond any doubt too. Hormones are another endogenous factor important for the development of some cancer types, including mammary gland tumours. The present review summarizes the available literature data about the etiology and risk factors for development of malignant tumours in dogs and cats. Key words : etiology, cat, dog, risk factors, tumours

INTRODUCTION

The share of malignant neoplasms in Cancer is a disease, which can affect vari- small animal pathology (dogs and cats) is ous organs and tissues in the body. There incessantly increasing, motivating the is no single cause or condition that causes studies in the field of tumour pathology cancer. The disease is rather a conse- aiming to increase the survival time and to quence of many factors, which are active improve the quality of cancer patients’ in a certain period of time (Lyman, 1992). life. One of the commonest malignancies The development of cancer is a result of in dogs and cats are mammary gland tu- the action of various carcinogens (exoge- mours, skin tumours, osteosarcomas and nous factors), such as ionized radiation, haemopoietic tumours. chemical agents, and oncogenic viruses. A Malignant tumours are a pathological number of endogenous factors– genetic, hyperbiosis, the etiology and pathogenesis immune, and hormonal, are also impor- of which are not sufficiently clarified. tant. The fact that cancer is more com- Prevalence and etiology of the most common malignant tumours in dogs and cats monly observed in older patients, supports terman et al. , 2000). The occurrences of the concept that, over the course of time, a tumours in cats are half as much as in combination of factors leads to a normal dogs (MacVean et al. , 1978). The fre- cell’s transformation into a cancer cell. quency of occurrence in cats is 158–470 / Each of these factors increases the likeli- 100,000 animals, while for dogs it is 381– hood for the appearance of cancer, and 1126 / 100,000 (Cullen et al. , 2002). they are therefore called risk factors Around 35 −45% of all tumors in cats are (Lyman, 1992). The significance of risk of the type that affects the skin and the factors in the development of cancer is soft tissues, while haemopoietic malig- based on their ability to influence the nancies constitute 30 −40% of the whole genes inside the cells (Lyman, 1992). (Hardy, 1981). Mammary gland tumours in cats are third in prevalence, after hae- mopoetic and skin tumours (Misdorp et PREVALENCE OF MALIGNANT TU- al. , 1999; Moulton, 1990). Approximately MOURS IN DOGS AND CATS 86% of all feline mammary gland tumours are malignant (Carpenter et al. , 1987; Malignant tumours affect both humans Hahn & Adams, 1997). With the excep- and animals. Cancer is among the leading tion of mammary tumors, which are more causes for death among pets (Proschow- often encountered in sexually intact fe- sky et al. , 2003; Bonnett et al. , 2005). In a males than in males and spayed females, series of more than 2000 autopsies, it was no relation between gender and the ap- found that 45% of the dogs that lived for pearance of tumours in cats could be 10 or more years, died because of cancer found (Gabor et al. , 2000). The average (Bronson, 1982). Dogs are affected by age of peak prevalence of tumours in cats skin cancer 35 times more often than hu- is approximately 9.3 years (Roccabianca mans are. They are also affected 4 times et al. , 2006; Tomek et al. , 2006). Mam- more often by mammary gland cancer, 8 mary tumours can also affect male cats, times more often by bone cancer, and with the average age for them being 12.8 twice more often by leukaemia, than peo- years (Skorupski et al. , 2005). Breed pre- ple do (Cullen et al. , 2002). disposition has been found in Siamese and Mammary gland tumours are the most Oriental cat breeds, which fall under frequently encountered group of neo- greater risk (Louwerens et al. , 2005; Ga- plasms in dogs (Moulton, 1990). They bor et al. , 2001). constitute 52% of all neoplasms in female Second in prevalence are skin tu- dogs (Brodey et al. , 1983). Between 41% mours. They make up 30% of neoplasms (Hahn & Adams, 1997) and 53% (Brodey in dogs (Priester, 1973). In dogs, these et al. , 1983; Rutterman et al. , 2000) of mammary tumours found in dogs are specific tumours have a share of 15 −20% malignant. Male dogs can also be affected of the total (Carpenter et al. , 1987). by mammary gland cancer, although the Around 55% of skin tumors in dogs origi- cases with them are much less than the nate from the mesenchymal tissues, the cases with female dogs − only 1%, (Rut- other 45% − from the epithelium (Priester, terman et al. , 2000). Mammary cancer is 1973). The commonest of the mesenchy- the commonest among dogs between 10 mal tumors in dogs are the histiocytomas, and 11 years of age, with neoplasms rarely lipomas, fat tissue cells tumors, and the seen in dogs less than 4 years of age (Rut- fibrosarcomas (Carpenter et al. , 1987;

86 BJVM, 9, No 2 I. Todorova

Miller et al. , 1991). In Siamese cats, fat aim of increasing the time of survival and tissue tumors are encountered three times quality of life of patients affected by ma- as much as in other feline breeds (Miller lignant neoplasms. et al. , 1991). Of the epithelial skin tumors in dogs, the most prevalent are tumours in ETIOLOGY AND RISK FACTORS the fat tissue cells and papillomas, while in cats, the most prevalent are basal cell tumours, and squamous cell carcinomas Gene mutations as a commencement of (Carpenter et al. , 1987; Miller et al. , carcinogenesis 1991). At cellular level, the cancer is character- Osteosarcomas are another frequently ized with uncontrolled cell growth. Cancer encountered malignancy in dogs, diag- cells undergo a process of transformation nozed in 50 −90% of all primary bone tu- from normal to malignant phenotype, with mors (Cooley & Waters, 1997; Jonge- ability for autonomous growth (Loeb & ward, 1985). They show a tendency for Loeb, 2000). A number of theories at- occurrence in giant dog breeds, and at a tempt to explain malignant transforma- younger age, in comparison with small tions of normal cells: dog breeds of weight under 15 kg, where • Mutations can change the genetic na- only adult animals are affected (Chun & ture of somatic cells, through which Lorimier, 2003). The highest frequency of cell death and proliferation are con- development of osteosarcoma is observed trolled (Jefford & Irminger-Finger, in large dog breeds, at the age of 7 years 2006). (Heyman et al. , 1992), while in small • Atypical differentiation of normal cells breeds, that age is 10.5 years (Cooley & is a result of the action of agents, Waters, 1997). which lead to changes in cell differen- One of the commonest haemopoietic tiation and to destruction of cellular tumours in dogs and cats is lymphoma regulatory mechanisms (Zavadil et al. , (Ettinger, 2003). The incidence of malig- 2004). nant lymphoma in cats is 6 times higher than in dogs (Schneider, 1983). According • Normal cell genes, called protoonco- to Schneider (1983) the spaying of female genes, acquire the ability to induce cats reduces the risk of development of neoplastic transformation (Spandidos, this tumour type by 50%, but doesn’t have 1985). a similar effect in bitches. Genes are responsible for the control In our country, retrospective studies of of normal functions within cells. Often tumour epidemiology in dogs reveal that changes in the deoxyribonucleic acid mammary tumours are prevalent, and that (DNA) building those genes occur (Loeb Bolognese dogs, above eight years of age & Loeb, 2000). These changes (genetic are the most affected, with over 60% ma- mutations) can carry into effect cellular lignancy (Dinev et al. , 2002). The epide- processes. The changes in the DNA in- miology of tumours in cats has not yet formation could be accidental, as a result been studied in our country. of infectious agents, or a consequence of These statistical data provide a ration- other agents, causing damage to DNA ale for more research to be performed in (Loeb & Loeb, 2000). In many cases, cells the field of tumour pathology, with the are capable of locating and repairing mutations before the cell is damaged. For

BJVM, 9, No 2 87 Prevalence and etiology of the most common malignant tumours in dogs and cats instance, the so-called tumour-suppressor carcinomas in dogs showed a p53 gene genes code special cell proteins that stop mutation. A long-term analysis has shown cell replication if its DNA is damaged that p53 gene mutations are independent (Ghosh & Bose, 2005). When this system risk factors for the higher risk of recur- of defense is functioning, a cell with DNA rence of mammary carcinoma (Wakui et mutation could not transmit the defective al. , 2001). genetic material to daughter cells. In a Other significant genes are the pro- case of low-degree damage, the cell con- tooncogenes, which enhance DNA synthe- tinues its growth cycle after the damage is sis, cell growth and division. These genes being removed. If the damage is too ex- are necessary during the individual’s de- tensive, then a process known as pro- velopment, and, afterwards, to support the grammed cell death (apoptosis) is trig- new growth of cells that replace the old or gered that results in self-destruction of the damaged cells. If these genes are activated cell (Steller, 1995; Ghosh & Bose, 2005). in the conditions of a mutation, they are In a case where tumor-suppressing genes transformed into oncogenes, and they (coding proteins that inhibit the synthesis would make cells grow and divide infi- of DNA, the cell growth and division) nitely (Spandidos, 1985). Such oncogene undergo a mutation, the cell growth could is p185, which was found in canine ma- be unlimited (Ghosh & Bose, 2005). Such lignant mammary gland tumors, and is a tumor-suppressor gene is p53 that plays considered as a poor prognostic sign an important role in carcinogenesis via (Schafer et al. , 1998). regulation of cell proliferation, genome It has been determined that a breed stability, and programmed cell death predisposition towards malignant growth (Hainaut et al. , 1997). The cells inherit does exist (Priester & McKay,1980; Cul- two copies of each tumour suppressor len et al. , 2002). Dog breeds with a high (Ghosh & Bose, 2005). According to the rate of affected animals are Boxers, authors, the mutation of just one copy of Golden Retrievers, Rottweilers, Boston the р53 tumor-suppressing gene is needed Terriers, English Bulldogs, Cocker Span- to result in the development of cancer. iels, while breeds that exhibit a low inci- According to Wakui et al. (2001) the dence of disease are Beagles, Collies, mutations of the tumour-suppressor gene Great Danes (Priester & McKay,1980; p53 are related to the development of Cullen et al. , 2002). The breed peculiari- breast cancer in humans and canine ties determine the predisposition towards mammary tumours. In a study of dogs the growth of different kinds of tumours. with various tumour types, inactivation of Breeds such as Poodle, English Spaniel, the tumour-suppressor gene p53 was es- English Setter, and Terriers, exhibit a tablished (Setoguchi et al. , 2001). In men higher risk of mammary gland tumors, with breast cancer with evidenced altera- while for other breeds, such as Boxer and tions of the p53 gene, the prognosis is Chihuahua, that risk is minimal (Rodney poor. The studies of Lee et al. (2004) and & Page, 2001; Cohen et al. ,1974). In a Haga et al. (2001) showed that in dogs, similar fashion, giant breeds such as Saint the p53 gene mutation is a sign of in- Bernard, and Great Dane are affected creased malignant potential and a bad much more frequently by osteosarcomas, prognostic sign for mammary gland tu- in comparison with dogs of smaller sizes mors. About 17 % of mammary gland (Chun & de Lorimier, 2003). Cats and

88 BJVM, 9, No 2 I. Todorova dogs with white skin and hair develop skin tooncogenes in the DNA of infected cells carcinomas under the influence of ultra- (Sourvinos et al. , 2000). This integration violet rays. Black and dark-pigmented of alien DNA may change the protoonco- animals suffer more from melanomas genic DNA. When this happens, protoon- (Rosenthal, 1998). The reason for this cogenes are transformed into oncogenes natural predisposition is not known, how- (Sourvinos et al. , 2000). The protein co- ever some dogs do inherit abnormal genes ded by the action of the protooncogenes is (oncogenes), selected together with the also structurally and functionally changed, sought genetic traits coding the morpho- and could lead to a normal cell’s trans- logical features of the breed (Sorenmo, formation into a cancer cell (Sourvinos et 2003). al. , 2000). As a conclusion, the inactivation of It was determined that the most fre- tumor-suppressor genes or the activation quently encountered neoplasm of the of oncogenes, the changes within other haemopoietic system in cats, the lym- genes demanding the correction of dam- phoma, is related to a retroviral infection aged DNA, or apoptosis are among the (FeLV) (Louwerens et al. , 2005). prime causes for normal cells to transform Chemical carcinogens. Unlike viral in- into cancer cells (Spandidos, 1985; fections, which can only be related with Anderson et al. , 1992; Hainaut et al. , several specific cancer diseases, chemical 1997). carcinogens are involved in the development of most cancer conditions (Loeb & Exogenous carcinogens Loeb, 2000). There are two groups of These are environmental factors – exoge- chemical carcinogens – direct and indirect nous carcinogens − viral agents, chemi- (procarcinogens). Indirectly acting car- cals, and physical factors. cinogens, contrasting to former ones, re- Tumour viruses. Some DNA viruses quire a metabolic activation by enzymes (herpes-, papova-, and adenoviruses) and normally present in the body, in order to RNA (ribonucleic acid) viruses (retro vi- become carcinogenic (Wild & Kleihues, ruses) are known as tumour viruses, since 1996). Indirect activation usually occurs they are proved to be causing cancer in during normal physiological processes, cells they have infected (Bishop, 1980; when the body eliminates toxic substances Madewell & Theilen, 1987). It was found in the bloodstream. Many toxic substan- that DNA viruses more frequently deter- ces, to which the body is exposed daily, mine the development of benign tumors in are insoluble, which requires that the dogs and cats – fibromas, papillomas, and liver, one of the most important organs other, while RNA viruses induce malig- responsible for the filtration of blood, to nant tumors (Gabor et al. , 2001; convert the insoluble substances through Louwerens et al. , 2005; Terai & Burk, enzyme reactions into soluble, so that they 2002). Such tumour viruses were found in can be eliminated by the body. Some toxic skin cancer (Allison, 1965; Sourvinos et substances require a longer reaction time al. , 2000; Terai & Burk, 2002), leukae- in order to be turned into soluble metabo- mia, and mammary gland tumours (Sour- lites. If these metabolites are highly reac- vinos et al. , 2000). They initiate tumours tive molecules, they can alter cell DNA by integrating their own genetic material before being removed from the body. inside, or close to the location of the pro-

BJVM, 9, No 2 89 Prevalence and etiology of the most common malignant tumours in dogs and cats

The following substances have a rela- radiation (Upton, 1978). Subcategories of tion with carcinogenesis (Palmer & Ma- ionized radiation are electromagnetic ra- thews, 1986): diation, as well as X-rays and γ-rays, and • Nitrates and nitrites. They are con- corpuscular radiation, which includes tained in many foods and in the organ- electrons, protons, neutrons, α-particles, ism could be transformed into N- heavy ions. Ionized and ultraviolet radia- nitroso compounds, most of which are tion alter DNA, interacting with its cellu- carcinogens for many laboratory ani- lar replication and suppressing its infor- mal species. Epidemiological studies mation, coding cellular proteins (Lyman, show that those compounds can be 1992). A typical event for ionized radia- carcinogens for humans as well. Acry- tion is the emission of enough energy to lonitrites and polyvinylchloride, used break the chemical bonds (Vasilenko et as packing material for food have a al. , 1986). Ionized radiation (atomic parti- strong carcinogenic effect on rodents. cles and X-rays) cause cleavage of DNA • Polycyclic aromatic hydrocarbons. bonds, while ultraviolet radiation causes These are compounds produced during chemical changes in amino acids, which smoking and food baking, and they build up DNA (Guzman, 2003). The na- have carcinogenic effects on labora- ture of the damage caused by ionized ra- tory animals. diation is such that it is very hard to be • Polychlorinated biphenyls: The are corrected by cell mechanisms because found in fish and meat, and are carci- during correction, the segment of broken nogenic for rodents, producing liver DNA can attach itself to another broken tumors. segment, and disrupt the sequence of basic According to Ames et al. (1990) natu- base ordering. ral chemicals are found in food, which can The oncogenic effect of ionized radia- lead to damages in DNA and induce cell tion depends on the individual doze, the alterations. The intake of such natural type of radiation, and the way it was re- DNA-damaging chemicals with food is leased (Lyman, 1992). It is considered much greater than that due to exposing that X-rays and γ-rays are the cause for the body to chemicals originating from the production of highly reactive mole- industry (Ames et al. , 1990). cules, such as free radicals. The released It has been determined that the expo- energy causes an electron to be moved sure of dogs to herbicides used in garden- from О 2 and the formation of the free su- − ing is a risk factor for the development of peroxide anion radical (·О2 ), which can urinary bladder carcinomas (Glickman et cause damage of DNA (Biaglow, 1981). al. , 2004). In dogs living in industrial ar- Free radicals are formed in the body as a eas, the age boundary of the commonest product of natural biological processes tumour diseases is significantly lowered within it, but are immediately neutralized (average 6.1 ± 0. 4 years) (Gavazza et al. , by the natural antioxidant protection me- 2001). chanisms. In the cases when the balance Physical carcinogens. This group in- between produced free radicals and active cludes radiation, foreign bodies, and hy- antioxidants is impaired, oxidative stress perthermia. There are two types of radia- occurs. The increased level of free radi- tion, which have significance in the etiol- cals in the body or a lowered antioxidant ogy of cancer – ultraviolet and ionized protection can cause DNA damage and

90 BJVM, 9, No 2 I. Todorova direct inhibition of proteins (Chopra & (Schafer et al. , 1998). The inherited ge- Wallace, 1998). One of the most reactive netic anomalies reduce the latent period free radicals – the hydroxyl radical (·ОН −) because the body already has internal vul- can capture electrons from tyols, thus in- nerability alterations and a single external teracting with the nitrogen bases of nu- influence could be suffucient for the trans- cleic acids and changing the genetic in- formation of normal cells into cancer formation of the cell, i.e. it possesses a cells. potential for tumour genesis (Castillo et Inherited genetic defects usually ap- al. , 2002). pear as foetal mutations, when genes con- Several studies have shown that there trolling tumor suppression are inactive, or are more cases of chronic leukaemia, thy- oncogenes in the semen or the ovum of roid tumours, breast cancer in humans the parents are active. exposed to radiation and increased inci- Little is known about the inheritance dence of lung cancer after exposure to factors of tumour development in dogs radioactive ore (a typical condition for and cats. Studies in this field are contro- miners) (Kohn & Fry., 1984). In dogs, versial. Inherited mutations of BRCA 1 radiation-induced tumours appear in 30 to and BRCA 2 genes were found in studies 78 months after radiation therapy (Thrall on dogs affected by mammary gland can- et al. ,1981; Thrall et al. ,1983). Such cases cer (Schafer et al. , 1998). At the same are very rare and they should not be a time, research by Lloyd et al. (2005) cause to refuse radiotherapy. In dogs and showed no clear data on the genetic in- cats, ultraviolet sun radiation can lead to heritance of canine mammary cancer. the appearance of squamous cell carcino- Immune system. It is believed that the mas (Dorn et al. , 1971; Madewell et al. , immune system can also be involved in 1981). It has been proved that ultraviolet the identification and elimination of cells, radiation is a strong carcinogen for the which undergo transformation from nor- occurrence of skin cancer in dogs, acting mal into cancer cells – a process known as simultaneously as an inducer and pro- immune surveillance. For example, many moter (Guzman et al. , 2003). of the very young or very old animals have reduced immune responses and ex- Endogenous factors hibit higher vulnerability towards the ac- To this group, genetic, immune and hor- tion of carcinogens. Animals, whose im- monal factors are belonging. mune systems are deliberately suppressed, Inherited genetic defects . Usually, exhibit higher probability to be affected cancer diseases caused by external car- by cancer when exposed to carcinogens, cinogens appear in older patients, while in comparison with non-suppressed ani- cases caused by inherited genetic defects mals, whose immune systems were stimu- occur in younger patients. During a study lated. For example, dogs with innate im- on two families of dogs, with strongly mune deficiencies suffer a 2 −4% higher differing phenotypes, one of which with frequency of cancer (Rosenthal, 1998). known predisposition, the other exhibiting The cellular immune response is mainly resistance towards tumour development, it involved in the process, and the role of the was determined that the average age of humoral immunity is not yet clear tumour incidence of the first family was (Rosenthal, 1998). The primary immu- significantly lower than in the other one nological factor, which has a relation to-

BJVM, 9, No 2 91 Prevalence and etiology of the most common malignant tumours in dogs and cats wards the spread of tumors is the activity not high whereas the level of PR in these of the natural killer cells (NK cells) (Ben- tissues was significant (Martin de las Mu- Eliyahu & Page, 1992). Acute pain sup- las et al. , 2002). The cause and the sig- presses the cytotoxicity of the NK cells, nificance of this fact are not known, but it and promotes tumour development in could influence the choice of therapy. In animals (Page et al. , 2001). cats treated with gestagens for oestrus Hormonal factors. Hormones are an- control, the development of mammary other endogenous factor playing an impor- cancer is much more likely to occur (Rod- tant role in the development of various ney & Page, 2001). neoplastic types, including mammary tu- The treatment of dogs with some hor- mours. In young animals, due to the activ- monal drugs as oestrogens and gestagens ity of hormones, cells could divide, thus could also increase the risk of mammary the organs and the organism as a whole tumours appearance. Oestrogens and pro- grow and develop. In adult animals, hor- gesterone are hormones with a strong mones control the cell growth in various stimulatory effect in canine mammary aspects of the reproductive cycle in both cancer (Key & Pike, 1982). The risk for male and females. In the presence of acti- development of mammary neoplasms in vated oncogenes or inactivated tumour- bitches is 0.05% if they are spayed prior suppressor genes into the cells, hormones to their first estrus (about the age of 6 are factors that would stimulate abnormal month), 8 % − if spayed after the first cells to divide and to become tumouro- oestrus and 26 % after the second one genic. That is why, it is supposed that the (Schneider et al. , 1969). The incidence of excessive stimulation of some organs by mammary tumours in intact bitches is hormones increased the probability of seven times higher compared to dogs development of neoplasms in them (Rod- spayed at the age of 2 years or earlier ney & Page, 2001). (Dorn, 1968; Sorenmo, 2003). The early Canine mammary tumours are hor- castration could reduce the number of monally dependent. Various studies upon malignant incidents, because the source of the hormonal effects in tumour genesis hormones is surgically removed. The showed that between 50% and 60% of all hormones are causing some mammary malignant mammary tumours in bitches cells to lose their controlled growth ex- contain estrogen receptors (ER) (Sobczak- posing them to increased risk of mutation Filipiak & Malicka, 2002), more than 30 and malignant transformation under the % − progesterone receptors (PR) and carcinogenic environmental influence (So- more than 20% − androgen receptors. Al- renmo et al. , 2000). so, these receptors were present in about The timing of ovarihysterectomy is 70% of benign mammary tumours (Mac- also important for the time of survival in Ewen et al. , 1982; Martin et al. , 1984; dogs (Sorenmo et al. , 2000). The expo- Donnay et al. , 1993). According to other sure to estrogens or the use of hormonal studies, only malignant tumours hold ER combinations in the first few years proba- (Geraldes et al. , 2000). In cats, mammary bly initiates the tumour development, the tumours are also common, but the role of neoplasms being not clinically manifested hormones in their development in not for years (Lemon, 1977). quite clear. Unlike dogs, the level of ER Sexually intact cats are also at a higher in feline malignant mammary tumours was risk for mammary tumour development vs

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