key: cord-0880340-n39rs4vq
authors: Madsen, Thomas; Arnal, Audrey; Vittecoq, Marion; Bernex, Florence; Abadie, Jerôme; Labrut, Sophie; Garcia, Déborah; Faugère, Dominique; Lemberger, Karin; Beckmann, Christa; Roche, Benjamin; Thomas, Frédéric; Ujvari, Beata
title: Cancer Prevalence and Etiology in Wild and Captive Animals
date: 2017-02-24
journal: Ecology and Evolution of Cancer
DOI: 10.1016/b978-0-12-804310-3.00002-8
sha: e0bb1672392f5d6b3a7a56c300cc41deb25b2e1f
doc_id: 880340
cord_uid: n39rs4vq

Neoplasia has been recorded in the vast majority of metazoans. The frequent occurrence of cancer in multicellular organisms suggests that neoplasia, similar to pathogens/parasites, may have a significant negative impact on host fitness in the wild. This is supported by the fact that wildlife cancers have recently been shown to result in significantly increased levels of mortality and concomitant reduction in fitness. By thorough searches of the available literature we provide a comprehensive and an updated list of cancer prevalence and etiology in the wild. We were, however, unable to find data on nontransmissible cancer prevalence in invertebrates and consequently this chapter focuses on cancer in wild vertebrates. Although single cases of cancer are frequently encountered in the wildlife, we were only able to retrieve robust data on cancer prevalence for 31 vertebrate species (12 fish, 3 amphibians, 2 reptiles, 2 birds, and 12 mammals). Cancer prevalence among these vertebrates ranged from as low as 0.2% observed in Canada geese (Branta canadensis) to more than 50% recorded in both Santa Catalina Island foxes (Urocyon littoralis catalinae) and Cape mountain zebras (Equus zebra zebra). The high prevalence recorded in some vertebrates strongly suggests that cancer in wildlife may indeed carry significant fitness costs. In spite of this, the low number of published comprehensive studies clearly shows that so far cancer in wildlife has received insufficient attention by biologists. We hope that this chapter will act as a catalyst for further studies focusing on the impact of cancer in wild animals. The chapter additionally compares cancer recorded in French zoological parks to those obtained at other zoological parks. Finally, we provide an updated list of cancer recorded as single cases in the wild, as well as in captive animals.

Despite the evolution of numerous natural cancer suppressor mechanisms (DeGregori, 2011), neoplasia has been recorded in most metazoans (Leroi et al., 2003) . Although, a few exceptional species, such as the naked mole-rat (Heterocephalus glaber) and sharks have been claimed to be resistant to cancer (Finkelstein, 2005; Tian et al., 2013) . Recent studies have, however, shown that even these species may develop cancer (Delaney et al., 2016; Finkelstein, 2005) strongly suggesting that the vast majority of multicellular organisms are indeed susceptible to cancer. The frequent occurrence of cancer in metazoans suggests that neoplasia, similar to pathogens/parasites, may have a significant negative impact on host fitness in the wild (Vittecoq et al., 2013) . This is supported by a recent review of wildlife cancer by McAloose and Newton (2009) demonstrating that high prevalence of cancer in, for example, Tasmanian devils (Sarcophilus harrisii) and belugas (Delphinapterus leucas) resulted in concomitant significant increase in levels of mortality and reduction in fitness.

Wildlife cancer statistics are, however, highly scattered in the scientific literature and hence challenging to access. Moreover, tumors in wildlife are most commonly detected during postmortem examination and therefore hard to confirm without histopathological examinations. However, even such analyses can be inaccurate because of high levels of autolysis (organ disintegration) (McAloose and Newton, 2009 ). In addition, individuals harboring tumors often display a decrease in body condition frequently resulting in higher levels of parasite/pathogen infections and concomitant increased levels in morbidity and mortality (Vittecoq et al., 2013) further impeding a correct analysis of the ultimate cause of death. The combination of the negative effects of cancer and/or pathogen/parasite infections has also been shown to result in increased levels of predation (Vittecoq et al., 2013) . In our view, the combination of the problems involved in accurately recording wildlife cancer, the increased risk of succumbing to pathogens/ parasites, and/or predation has often led to a somewhat erroneous assumption that although cancer is common in domestic animals, it remains rare in the wild. If, as we suggest, cancer may be a significant determinant of animal fitness it is therefore crucial to determine cancer prevalence in the wild.

The etiology and prevalence of transmissible cancers are presented and discussed in Chapter 12; this chapter will therefore focus on the prevalence and etiology of nontransmissible cancers.

Via thorough searches of the available literature we provide a comprehensive and an updated list of cancer prevalence in wild animals ranging from fish to whales. We also provide a list of cancer recorded in captive animals from French zoological parks and compare our findings to that recorded at other zoological parks. Finally we provide an updated list of cancers recorded as single cases in the wild, as well as in captive animals demonstrating that cancer occurs in nearly every taxonomic order of the animal kingdom.

Although cancers are frequently encountered in wild animals (see Table 2 .1 starting on page 13), we were only able to retrieve robust data on cancer prevalence in 31 wild vertebrate species (Table 2. 2). We were unable to find information on nontransmissible cancer prevalence in wild invertebrates and consequently this chapter focuses on cancer in wild vertebrates ranging from fish to mammals. In following sections, we provide a summary of cancer etiology and prevalence in each of the five vertebrate groups (Table 2 .2).

Fish FAO (2010) fisheries and aquaculture department published a report showing that the mean contribution of fish to global diets was 17 kg per person/year, supplying over three billion people with 15% of their animal protein intake. About 45% of the fish consumed were farmed but the remaining 55% of fish were caught in the wild clearly demonstrating the importance of wild fish in the human diet. In spite of their importance to humans we have only been able to find information on cancer prevalence in 12 wild fish taxa.

In walleye (Sander vitreus) and Atlantic salmon (Salmo salar) retroviruses have been found to initiate cancer development (Coffee et al., 2013) . In bicolor damselfish (Stegastes partitus) neurofibromatosis-like tumors are most likely caused by an "extrachromosomal DNA virus-like agent" (Coffee et al., 2013) whereas in European smelt (Osmerus eperlanus) cancer development have been suggested to be caused by a "herpesvirus-like agent" (Coffee et al., 2013) . In northern pike (Esox lucius) a corona virus has been suggested to be the cause for the development of lymphosarcoma (Papas et al., 1976 ). This species also shows substantial seasonal variation in lymphosarcoma prevalence but the underlying etiology is unknown (Papas et al., 1976) . In brown bullhead (Ameiurus nebulosus), however, the higher levels of liver neoplasms (15%) recorded on one of the lakes investigated have been suggested to be caused by pollution (Baumann et al., 2008) . Similarly, a study of English sole (Parophrys vetulus) revealed that up to 24% of the fish had developed liver neoplasms of which etiology could be traced to have been caused by pollution/chemical carcinogens (Malins et al., 1987) .

Cancer prevalence as high as 20% have been observed in several species, such as gizzard shad (Dorosoma cepedianum), northern pike, walleye, bicolor damselfish and in white sucker (Catostomus commersoni) cancer may affect up to 59% of the fish (Coffee et al., 2013) . However, the epidermal papilloma recorded in the latter taxon appears to result in low mortality (Coffee et al., 2013) . In contrast, cancers, such as plasmacytoid leukemia have been shown to result in up to 50% mortality in commercially important taxa, such as Chinook salmon (Oncorhynchus tshawytscha; Eaton et al., 1994) and neurofibromatosislike tumors have been shown to result in 100% mortality in bicolor damselfish (Coffee et al., 2013) . Apart from the latter two studies, the remaining studies do not provide any data on the effect of cancer on fish mortality. In spite of this we find it reasonable to suggest that the high tumor frequency observed in several species may have a significant negative impact on fish fitness. Given the importance of fish in the human diet the high cancer prevalence and associated mortality recorded in some fish taxa, clearly demonstrate the need of a substantial increase in research on the effect of cancer on both marine and freshwater fish.

Although cancer has been reported in numerous amphibians (Balls and Clothier, 1974) we have only been able to find three studies that incorporated data on cancer prevalence in the wild. In the North American leopard frog (Rana pipiens) McKinnel (1965) found that 

Common name

Paralithodes platypus Blue king crab Anaplastic cells on the surface of the antennal gland, probable tegmental gland adenocarcinoma Morado et al. (2014) Insecta

Fruit fly Gut and testis tumors Salomon and Jackson (2008) 

Armed bullhead Dermal fibromas, fibrosarcomas Groff (2004) Amia calva Bowfin Granuloplastic leukemia Groff (2004) Anguilla japonica Japanese eel Nephroblastoma Groff (2004) Astronotus ocellatus Oscar Adenocarcinomas Groff (2004) Barbus barbus plebejus Italian barbel Osteoblastic osteosarcoma Groff (2004) Carassius auratus Goldfish Fibrosarcoma, pigment cell neoplasm, neurofibromas, schwannomas, focal or multifocal cutaneous erythrophoromas Groff (2004) Carassius auratus × Cyprinus carpio Goldfish hybrid Gonadal neoplasms Groff (2004) Carcharhinus brachyurus Bronze whaler shark Proliferative, possibly neoplastic, lesions Robbins et al. (2014) Carcharhinus leucas Bull shark Cutaneous neoplasms Robbins et al. (2014) Carcharias taurus rafinesque Gray nurse shark Odontogenic, oral, and gingival neoplasms Robbins et al. (2014) Carcharodon carcharias Great white shark Proliferative, possibly neoplastic, lesions Robbins et al. (2014) Catostomus commersoni White sucker Cutaneous papillomas Groff (2004) Chaetodon multicinctus and C. miliaris

Butterflyfish hybrids Pigment cell neoplasms Groff (2004) Chologaster agassizi Spring cavefish Spontaneous retinoblastomas Groff (2004) Corydoras spp. Cory catfish Pigment cell neoplasms Groff (2004) Cyprinus carpio Common carp Gonadal neoplasms, erythrophoromas Groff (2004) Mader (1996) Crotalus horridus Timber rattlesnake Adenoma, adenocarcinoma, fibrosarcoma, leukemia, mesothelioma, hemangioma Mader (1996) Crotalus mitchellii pyrrhus Southwestern speckled rattlesnake Adenocarcinoma Mader (1996) Crotalus ruber Red diamond rattlesnake Sarcoma Mader (1996) Crotalus viridis helleri Prairie rattlesnake Hemangioma Mader (1996) Crotalus viridis viridis Prairie rattlesnake Fibrosarcoma Mader (1996) 

Elaphe obsoleta Western rat snake Adenocarcinoma, adenoma, fibrosarcoma, rhabdomyosarcoma Mader (1996); Catão-Dias and Nichols (1999) Elaphe obsoleta rossalleni Everglades rat snake Melanoma Mader (1996) Elaphe obsoleta quadrivittata Yellow rat snake Transitional cell carcinoma Mader (1996) 

Mexican milk snake Sarcoma Mader (1996) Lampropeltis triangulum sinaloae Sinaloan milk snake Myxosarcoma, sarcoma, hepatoma Mader (1996) ; Catão-Dias and Nichols (1999) 

Indian rock python Ameloblastoma, fibroma Mader (1996) Python molurus bivittatus Burmese python Carcinoma, adenocarcinoma, interstitial cell tumor, osteosarcoma Mader (1996) Python molurus molurus Indian python Sarcoma, lymphoma, leukemia Mader (1996) Python regius Ball python Fibrosarcoma Mader (1996) Python reticulatus Reticulated python Carcinoma, melanoma, lymphoma Mader (1996) Python sebae African rock python Adenoma Mader (1996) Rhamphiophis oxyrhynchus Rufous beaked snake Hemangiosarcoma, lymphoma, fibrosarcoma Catão-Dias and Nichols (1999) Sistrurus catenatus Massasauga Adenoma, hemangioma, carcinoma Mader (1996) Spilotes pullatus Yellow rat snake Adenocarcinoma Mader (1996) Strophurus spinigerus Spiny-tailed gecko Neuroblastoma Ladds (2009) Terrapene carolina Common box turtle Adenocarcinoma Mader (1996) Testudo graeca Spur-thighed tortoise Adenoma Mader (1996) Testudo hermanni Hermann's tortoise Lymphoma, neurilemmoma Mader (1996) Testudo horsfieldii Afghan tortoise Fibroma, fibroadenoma Mader (1996) Thamnophis sauritus Ribbon snake Lipoma Dietz et al. (2016) up to 9% of the frogs were diagnosed with renal adenocarcinoma in 1965. However, no information about tumor etiology or its possible effects on the frogs was provided. Interestingly, in a later study McKinnell and Martin (1979) observed a gradual temporal decline in tumor prevalence and in 1978 no tumors were observed in 1216 dissected frogs. McKinnell and Martin (1979) suggested that the decline in cancer prevalence was caused by a significant reduction in frog numbers and a concomitant reduction in the release of oncogenic viruses into the breeding ponds. However, the authors could not rule out that a gradual reduction of carcinogenic pollutants into the breeding ponds could have caused the decline in tumor prevalence. Asashima et al. (1982) studied the occurrence of spontaneous skin papillomas in Japanese newts (Cynops pyrrhogaster) in northern Japan. The prevalence of papillomas showed a seasonal variation, being highest in autumn, ranging from 1.93% to 5.45%, whereas during the rest of the year the prevalence ranged between 0.16% and 0.50%. A spatial difference in cancer prevalence was also recorded with newts collected from the northern, seaside prefectures having higher papilloma rates (1.00-5.45%) than newts from the southern, Pacific Ocean prefectures (0-0.27%). No intersexual differences in tumor prevalence were recorded. Virus-like bodies, resembling herpestype virus, were found in the cytoplasm of the epitheliomas, suggesting that tumor may have been caused by a viral agent. Unfortunately the study does not provide any information of the underpinning(s) of the temporal and spatial variation in tumor prevalence or whether the tumors affected newt mortality.

In a recent study skin tumor prevalence was investigated in the Montseny brook newt (Calotriton arnoldi) in Spain (Martinez-Silvestre et al., 2011) . The range of this taxon is restricted to a small geographic area <40 km 2 of the North Eastern Iberian Peninsula. Similar to the Japanese newt a profound spatial population difference in tumor prevalence was observed ranging from 0%, 2% to 29%. The tumors were only observed in adult newts, which led the authors to suggest that the tumors may be caused by increased UV-B exposure. Yet again no data are provided on whether the tumors may affect newt mortality.

Although our sample is small, it shows that cancer prevalence may affect a substantial proportion of wild amphibians. Considering the dramatic decline in amphibians caused by the chytrid fungus, Batrachochytrium dendrobatidis (Daszak et al., 1999) makes it even more important to further investigate the possible negative effects of cancer in this group of vertebrates.

The only reptile taxa for which we have been able to retrieve data on cancer prevalence in the wild are restricted to marine turtles. Although fibropapillomatosis (FP) mainly affects green turtles (Chelonia mydas) it has also been documented in loggerheads (Caretta caretta; Aguirre et al., 1999b) . Green turtles have been subjected to numerous and extensive research projects and here we summarize the major findings from some of these studies. FP in green turtles results in tumor growth on eyes, oral cavity, skin, carapace, plastron, and/or internal organs . Consequently the disease may significantly reduce turtle foraging efficiency. FP shows significant geographic variation not only in prevalence (ranging from 0% to 92%) but also in severity . Moreover, in Brazil the disease is absent in juvenile green turtles but increases in prevalence in older turtles . In contrast in Hawaii, FP affects mainly juvenile turtles (Balazs and Pooley, 1990; Work and Balazs, 1999) . However, the reason(s) for the agespecific increase in FP prevalence in Brazil and the agespecific difference in cancer development in Brazil and Hawaii is unknown. Interestingly, Chaloupka et al. (2009) reported on cases where FP had regressed and even completely disappeared in some individual green turtles in Hawaii, and that the diseases since the mid-1990s has showed a significant decline in prevalence.

Although we have not been able to find data on how FP affects green turtle mortality rates, the disease results in high parasite load, immune suppression, increased physiological cost (Work and Balazs, 1999; Work et al., 2001 Work et al., , 2005 and is the most common cause of green turtle stranding on Hawaii (Chaloupka et al., 2008 (Chaloupka et al., , 2009 ). Consequently, we find it highly likely that FP may impose considerable mortality cost on green turtles in the wild. In spite of FP's high prevalence in some areas and its possible severe effects on green turtle fitness the etiology of FP is still not known. Some studies have found an association between herpesviruses and FP (Greenblatt et al., 2005) , whereas others have implicated that pollution and habitat quality may be major factors explaining the presence of FP (Herbst and Klein, 1995) .

The detrimental impact of cancer on marine turtles and the emergence of a novel fungal disease in squamate reptiles (Guthrie et al., 2015) warrant increased research efforts to investigate how cancer might affect the demography of reptiles in the wild.

We find it remarkable that although birds are often abundant in both urban and rural habitats we have only been able to find a handful of studies that have recorded cancer prevalence in wild birds. Jennings (1968) estimated the prevalence of neoplasia in wild birds in Great Britain to be between 0.1% and 1.0%. Similar low cancer prevalence was recorded by Gates et al. (1992) in Canada geese (Branta canadensis interior; 2 out of 1272 birds, 0.2%). Both birds were young and emaciated and microscopical analyses suggested that the tumors "had the typical appearance of spindle cell sarcomas" (Gates et al., 1992) . Similar results on low cancer prevalence in wild birds were published by Siegfried (1983) who found tumors in only 9 out of more than 18,000 birds examined (0.05%). Although based on a significantly smaller sample size, 3 out of 13 (23%) ruffed grouse (Bonasa umbellus) were diagnosed having tumors (Howerth et al., 1986) . One bird was diagnosed with a lipoma, the second bird a fibroma, while the third bird had developed a renal carcinoma metastatic to the liver (Howerth et al., 1986) . The high prevalence recorded in ruffed grouse should, however, be interpreted with caution as all three birds were delivered for examination because they all suffered from obvious lesions. Reece (1992) reported 383 cases of cancer from a collection of more than 10,000 birds (3.8%) submitted for necroscopy in Victoria, Australia from 1977 to 1987. As the birds examined included both wild and captive birds and no data are provided on the number of birds in each of the two groups, again the data on cancer prevalence should be interpreted with caution.

The only publication we have found showing that cancer prevalence in birds may reach similar levels as that found among other vertebrates is a study by Daoust et al. (1991) who reported that out of 30 wild white-fronted goose (Anser albifrons) killed by hunters 7 (23%) were diagnosed as having developed multicentric mesenchymal tumors. Daoust et al. (1991) suggested that the high prevalence could have been caused by "a genetically influenced susceptibility to the disease." Unfortunately, however, no data are provided to support this statement.

In their review of wildlife cancer McAloose and Newton (2009) listed the endangered North American Attwater's prairie chicken (Tympanicus cupido attwateri) as an example of a species being further threatened by extinction due to cancer. Although reticuloendotheliosis virus may infect up to 50% of the captive birds, we have not been able to find any publication that relate this high infection level to mortality in the wild.

The few publications that we have been able to retrieve suggest that cancer prevalence in birds in general appears to be low. Although the sample size in some of the studies were very high, they were often restricted to large-bodied and long-lived species, such as geese. In order to make any robust generalization of cancer prevalence among wild birds, future research should incorporate birds representing a significantly more diverse taxonomic range.

Cancer prevalence and its effect on some wild mammal population, such as California sea lions (Zalophus californianus) and belugas (Delphinapterus leucas) have been subjected to intensive research (Gulland et al., 1996; Martineau et al., 2002) . Between 1979 and 1994 the prevalence of a metastatic carcinoma of urogenital origin in stranded California sea lions was reported to be 18% (Gulland et al., 1996) . However, between 1998 and 2012 the prevalence of this cancer increased to 26% (Browning et al., 2015) . This metastatic carcinoma appears to result in 100% mortality as all animals died during rehabilitation (Gulland et al., 1996) . The actual prevalence of this cancer is most likely lower as only sick animals are likely to strand, but despite this the cancer represents a significant cause of death (Browning et al., 2015) . Recent studies have found that the etiology of the cancer is associated with individual genotype, persistent organic pollutants, and/or a herpesvirus (Browning et al., 2015) . Similar high cancer prevalence has been recorded in an isolated beluga population living in the St. Lawrence estuary (Martineau et al., 2002) . Although the primary causes of death were respiratory and gastrointestinal infections with metazoan parasites, observed in 22% of the belugas, cancer was the second most common cause of death across all age groups and observed in 18% of the stranded belugas (Martineau et al., 2002) . Cancer prevalence in adults was even higher (27%) and Martineau et al. (2002) estimated the annual rate of all cancer types in belugas to 163 out of 100,000 animals, a rate significantly higher than that reported for any other cetacean populations and similar to that of recorded in humans. Beluga habitat in the St. Lawrence estuary is highly contaminated by polycyclic aromatic hydrocarbons produced by the local aluminum smelters, strongly suggesting that polycyclic aromatic hydrocarbons are a major cause of the high cancer prevalence recorded in this population (Martineau et al., 2002) .

High cancer prevalence has also been recorded in other marine mammals, such as Pacific walrus (Odobenus rosmarus divergens) and Baltic gray seal (Halichoerus grypus). In the former, 18 neoplasms were found during examination of tissues collected from 107 carcasses (17%) from Alaskan subsistence hunting over a 10-year period (Fleetwood et al., 2005) . However, no data regarding cancer etiology or pathogenesis of the walrus examined are presented. Between 1975 and 1997, 53 female Baltic gray seals aged between 15 and 40 years were found dead along the Baltic coast of Sweden, of which 34 (64%) where diagnosed having developed uterine leiomyomas (Bäcklin et al., 2003) . Although little is known about the etiology and pathogenesis of leiomyoma in Baltic gray seals, Bäcklin et al. (2003) tentatively suggested an association between cancer prevalence and pollutants, such as organochlorines. However, as mentioned earlier, the actual prevalence of uterine leiomyomas in female Baltic gray seals is most likely lower as only sick animals are likely to strand. Regardless, similar to the California sea lion, this cancer may constitute a significant cause of mortality in this species.

In contrast to the four marine species mentioned previously, neoplasia in northern sea otters (Enhydra lutris) appears to be rare and Williams and Pulley (1981) only found tumors in 2 females out of 112 otters examined (1.8%). Similar to the female Baltic gray seals, tumors of the female otters were diagnosed as uterine leiomyomas (Williams and Pulley, 1981) .

Our review of the literature also revealed significant geographical species-specific difference in cancer prevalence. For example, of 42 roe deer (Capreolus capreolus) carcasses examined in Hungary, 14 (33%) showed macrosopic lesions consistent with skin FP (Erdélyi et al., 2009) , whereas out of 985 carcasses examined in Sweden only 19 were diagnosed having neoplasia (2%) and only 1 of the 19 having developed FP (Aguirre et al., 1999a) . Moreover, within the Hungarian study neoplasia was confined to certain geographical areas (Erdélyi et al. 2009 ). As FP is caused by the infection of papillomavirus (CcPV1) this led Erdélyi et al. (2009) to suggest that genetic factors may underpin roe deer susceptibility to FP.

In humans increased cancer prevalence has shown to be associated with reduced genetic diversity (Assié et al., 2008; Rudan et al., 2003) . It is therefore interesting to note that some of the highest cancer prevalence's observed in wild mammals (>50%) have been recorded in species/populations with low genetic diversity, such as the Santa Catalina Island foxes (Urocyon littoralis catalinae; Funk et al., 2016; Vickers et al., 2015) and the South African Cape mountain zebra (Equus zebra zebra; Marais and Page, 2011; Marais et al., 2007; Sasidharan et al., 2011) . Vickers et al. (2015) suggested that the high prevalence of ceruminous gland tumors (carcinomas and adenomas) observed in the Santa Catalina Island foxes may have a genetic basis. Similarly, the high cancer prevalence observed in one of the South African Cape mountain zebra populations has also been suggested to be associated with concomitant low genetic diversity (Marais et al., 2007; Sasidharan et al., 2011) . Interestingly, as mentioned earlier, the high prevalence of cancer in California sea lions may also, at least partly, have a genetic basis (Browning et al., 2015) . The possible association between reduced genetic diversity and cancer prevalence is further supported by the high prevalence of cancer observed in both captive and wild western barred bandicoot (Perameles bougainville), a highly endangered Australian marsupial once widespread across western and southern Australia but now restricted to two small islands off the Western Australian coast (Woolford et al., 2008 (Woolford et al., , 2009 . Captive breeding of this species has been severely hampered by debilitating cutaneous and mucocutaneous papillomatosis and carcinomatosis, associated with infection of papillomatosis carcinomatosis virus type 1 (BPCV1) (Woolford et al., 2008 (Woolford et al., , 2009 .

Low genetic diversity in the wild has been found to result in increased risk of inbreeding depression and concomitant increased risk of extinctions (Madsen et al., 1996 (Madsen et al., , 1999 (Madsen et al., , 2004 . If low genetic diversity results in an increased risk of cancer, as suggested by the examples mentioned previously, this may further imperil the longterm survival of the numerous wild organisms presently suffering from low genetic diversity.

Although conditions (and hence associated cancer risks) in zoological parks are often significantly different from those experienced in nature (e.g., altered levels of activity and food and abnormal breeding frequency; Vittecoq et al., 2013) , cancer studies in captive animals are facilitated by the absence of masking variables, such as predation. In addition, because of curative and preventive improvements in veterinary medicine, diseases of captive animals are closely monitored and routine necropsies are performed using microscopy analysis (Hubbard et al., 1983; Lombard and Witte, 1959) .

The study was conducted from September 2013 to February 2015. Thirty zoological parks were contacted through a partnership with two French animal histopathology laboratories (ONIRIS in Nantes, VetDiagnostic in Lyon) and the French Association of Zoological Park Veterinarians (AFVPZ). Data collection consisted of (1) consultation of veterinarian archives in the zoological parks and (2) analysis of centralized data by veterinarian histopathology laboratories.

As accurate cancer diagnosis relies on histopathological examination of samples from biopsies, resection, or autopsy/necropsy (Martineau et al., 2002) , we therefore only entered tumor type (benign or malignant) into our database when they had been confirmed by histological analyses. We also recorded the organs affected, and, if any, the presence and the location of metastases. In order to facilitate data presentation, we classified the tumors into 12 anatomical systems.

The database consisted of 343 tumor references, including 271 cases of cancer in mammals, 46 in birds, and 26 in reptiles representing 27 different orders (Table 2. 3).

The tumor frequencies observed in the three vertebrate classes revealed remarkable similarities. High frequencies of digestive (18.4-34.8%), hematopoietic (17.6-27.9%), and skin tumors (14.2-18.6%) were observed in mammals, birds, and reptiles whereas tumors in the remaining 9 anatomical systems occurred in similar low frequencies (0-9.5%; Table 2 .4).

The prevalence of malignant tumors differed among taxa (χ 2 = 8.68, df = 2, P = 0.01; Table 2 .5) and posthoc tests revealed that reptiles had a higher prevalence of malignant tumors than mammals (P = 0.018), while no significant difference in prevalence of malignant tumors were observed between mammals and birds and reptiles and birds (P > 0.17). Accipitriformes (e.g., birds of prey) 2 Afrosoricida (e.g., tenrecs and golden moles) 2

Anseriformes (e.g., ducks and geese) 5 Carnivora (e.g., cats and wolves) 114

Bucerotiformes (e.g., hornbills and hoopoes) 3 Cetartiodactyla (e.g., pigs and deer) 49

Ciconiiformes (e.g., storks) 1 Chiroptera (e.g., bats and flying foxes) 4

Columbiformes (e.g., pigeons and doves) 3 Cingulata (e.g., armadillos) 2

Galliformes (e.g., turkeys and chickens) 2 Diprotodontia (e.g., kangaroos and koalas) 7

Gruiformes (e.g., cranes, coots, and rails) 1 Lagomorpha (e.g., hares and rabbits) 1

Pelecaniformes (e.g., pelicans and cormorants) 8 Perissodactyla (e.g., zebras and rhinoceros) 14

Phoenicopteriformes (e.g., flamingos) 2 Pilosa (e.g., anteaters) 2

Psittaciformes (e.g., parrots and parakeets) 10 Primates (e.g., monkeys and apes) 70

Rheiformes (e.g., rhea) 2 Rodentia (e.g., rats and capybaras) 6

Sphenisciformes (e.g., penguins) 3

Strigiformes (e.g., owls) 4

Order n

Crocodilia (e.g., crocodiles and alligators) 1

Squamata (e.g., snakes and lizards) 23

Testudines (e.g., turtles and tortoises) 2

The results from the present study show that the highest tumor prevalence was observed in the carnivores (42.1%, 114 of 271). Similar high cancer prevalence in this group of mammals was observed by Lombard and Witte (1959) and Effron et al. (1977) . Carnivores include both domestic cats and domestic dogs, of which both have been shown to be subjected to high prevalence of tumors (Merlo et al., 2008; Zambelli, 2015) . However, we have not been able to find any information explaining the high prevalence in these two groups of mammals. Our results also revealed similar levels of cancer prevalence in mammal digestive system (18.4%) to that recorded by Lombard and Witte (1959) (20%) . Moreover, the second most common tumors observed in mammals by Effron et al. (1977) was hematopoietic/ lymphosarcoma (8.9%) followed by skin tumors (8.7%). Our results thus again show a remarkable similarity with the results obtained by Effron et al. (1977) as we also found hematopoietic and skin tumors being the second and third most common tumors recorded (17.6 and 14.2%, respectively).

In contrast Lombard and Witte (1959) found that the second most prevalent tumors were confined to the endocrine system (18.4%) whereas in our study endocrine tumors were only found in 7.9% of mammals. Both Effron et al. (1977) and Lombard and Witte (1959) found that pulmonary tumors were the most prevalent cancer recorded (14 and 16%, respectively) whereas in our study pulmonary tumors were only found in 6.4% of the animal investigated that is, the 7th of the 12 anatomical systems.

Comparing our results of tumor prevalence in birds with those obtained by Effron et al. (1977) again revealed some striking similarities. In both studies hematopoietic/lymphosarcoma were the most prevalent tumors recorded (27.9 and 32.4%, respectively). In the studies by both Effron et al. (1977) and Lombard and Witte (1959) , as well as in our study the second most prevalent cancers were confined to the gastric/ digestive system (20.9, 22.2, and 12.6%, respectively). In all three studies the third most prevalent tumors were fibrosarcoma/skin tumors (18.6, 11.1, and 9.9%, respectively). In contrast the second most common tumors recorded by Lombard and Witte (1959) were confined to genital system (20.2%) whereas these tumors were the fourth most common tumors recorded by Effron et al. (1977) (9.9%) and the sixth most common tumors in our study (4.6%).

The most common cancers recorded by Effron et al. (1977) in reptiles were lymphosarcoma (25%) followed by tumors in the intrahepatic biliary/digestive system (21%). Again our results are quite similar to that recorded by Effron et al. (1977) although the order of the two cancer types was reversed, that is, our results showed a highest prevalence in the digestive system (34.8%) followed by the hematopoietic system (21.7%).

The high prevalence of cancers observed in our study affecting the digestive, hematopoietic, and skin systems recorded across the three vertebrate classes is remarkable and certainly warrants further studies to investigate whether these high prevalences also occur at other zoological parks. As these animals are kept under quite different conditions, that is, most mammals and birds are kept in outdoor cages whereas reptiles are mostly kept indoors we presently have no explanation for the similarities in tumor prevalences among these three groups of vertebrates.

The results from the present study suggest that malignant tumors in reptiles were more prevalent than that observed in mammals. However, this is not supported by the study of Effron et al. (1977) who did not find any significant difference in malignant tumors among the three vertebrate classes. As our data on tumor prevalence in reptiles are based on fairly small number of individuals we therefore suggest that our results should be interpreted with caution.

Although many of the results from the present study are similar to that observed by Effron et al. (1977) and Lombard and Witte (1959) we do emphasize that the cancer etiology and prevalence were all obtained from animals kept in captivity. Cancer in captive animals has been shown to develop predominantly in older age cohorts. For example, although cancer prevalence in captive black-footed ferrets (Mustela nigripes) has been shown to affect 55% of the ferrets, the cancer almost exclusively affected postreproductive animals (Lair et al., 2002) . The age-specific increase in cancer prevalence recorded in captive animals suggests that the significance of cancers recorded, similar to that recorded in black-footed ferrets, may therefore have limited or in some cases even no fitness effect in the wild. Regardless, cancer statistics recorded in captive animals remain an important source of information for studies in comparative oncology, as well as providing data on cancer etiology.

Observations of fibropapillomatosis in green turtles (Chelonia mydas) in Indonesia

Descriptive epidemiology of roe deer mortality in Sweden

Proceedings of the 19th Annual Symposium on Sea Turtle Biology and Conservation

Seasonal and geographical changes of spontaneous skin papillomas in the Japanese newt Cynops pyrrhogaster

Frequency of germline genomic homozygosity associated with cancer cases

Spontaneous malignant neoplasms in dasyurid marsupials

Histology of uterine leiomyoma and occurrence in relation to reproductive activity in the Baltic gray seal (Halichoerus grypus)

Marine Turtle Fibropapilloma Disease Workshop

Spontaneous tumors in amphibia

Neoplastic diseases of commercially important marine bivalves

Prevalence of Tumors in Brown Bullhead from Three Lakes in Southeastern Massachusetts

Characterization of a biphasic neoplasm in a Madagascar tree boa (Sanzinia madagascariensis)

Daily movements, habitat use, and submergence intervals of normal and tumor-bearing juvenile green turtles (Chelonia mydas L.) within a foraging area in the Hawaiian Islands

Common cancer in a wild animal: the California sea lion (Zalophus californianus) as an emerging model for carcinogenesis

Gastrointestinal diseases of marsupials

Spontaneous proliferations in Australian marsupials-a survey and review. 1. Macropods, koalas, wombats, possums and gliders

Neoplastic diseases of marine bivalves

Neoplasia in snakes at the National Zoological Park

Rise and fall over 26 years of a marine epizootic in Hawaiian green sea turtles

Cause-specific temporal and spatial trends in green sea turtle strandings in the Hawaiian Archipelago

Spontaneous neoplasms in zoo mammals, birds, and reptiles in Taiwan-a 10-year survey

The role of ras gene in the development of haemic neoplasia in Mytilus trossulus

Disseminated neoplasia in blue mussels, Mytilus galloprovincialis, from the Black Sea

Intracerebral malignant plasmacytoma in a mule deer

Pathology of tumors in fish associated with retroviruses: a review

Ameloblastoma in a wild black rat snake (Pantherophis alleghaniensis)

Multicentric intramuscular lipomatosis/fibromatosis in free-flying whitefronted and Canada geese

Emerging infectious diseases and amphibian population declines

Evolved tumor suppression: why are we so good at not getting cancer?

Initial case reports of cancer in naked mole-rats (Heterocephalus glaber)

Regional patterns in prevalence of principal external diseases of dab Limanda limanda in the North Sea and adjacent areas 1992-1997

Pulmonary angiomatosis and hemangioma in common dolphins (Delphinus delphis) stranded in Canary Islands

Cutaneous and subcutaneous soft tissue tumours in snakes: a retrospective study of 33 cases

Relationship between fibropapillomatosis and environmental quality: a case study with Chelonia mydas off Brazil

Biochemical and histologic evidence of plasmacytoid leukemia and salmon leukemia virus (SLV) in wild-caught chinook salmon Oncorhynchus tshawytscha from British Columbia expressing plasmacytoid leukemia

Nature and rate of neoplasia found in captive wild mammals, birds, and reptiles at necropsy

Massive distal forelimb fibromyxoma in a free-ranging American alligator (Alligator mississippiensis)

Endemic papillomavirus infection of roe deer (Capreolus capreolus)

The State of the World Fisheries and Aqualculture

Sharks do get cancer: few surprises in cartilage research

Incidence of ovarian tumors in hares in New Zealand

Fibropapillomatosis in stranded green turtles (Chelonia mydas) from the eastern United States (1980-98): trends and associations with environmental factors

Adaptive divergence despite strong genetic drift: genomic analysis of the evolutionary mechanisms causing genetic differentiation in the island fox (Urocyon littoralis)

Prevalence of spindle cell sarcomas among wild Canada geese from Southern Illinois

Pigmented skin tumors in gizzard shad (Dorosoma cepedianum) from the south-central United States: range extension and further etiological studies

Chemotherapy and radiotherapy for treatment of cutaneous lymphoma in a ground cuscus (Phalanger gymnotis)

Reports of oligodendrogliomas in three whitetailed deer (Odocoileus virginianus)

Genomic variation of the fibropapilloma-associated marine turtle herpesvirus across seven geographic areas and three host species

Neoplasia in fishes

Metastatic carcinoma of probable transitional cell origin in 66 free-living California sea lions (Zalophus californianus), 1979 to 1994

Detection of snake fungal disease due to Ophidiomyces ophiodiicola in Virginia, USA

High Ophidiomyces ophiodiicola a colony of Egyptian spiny-tailed lizards (Uromastyx aegyptius)

An oncologist's friend: how Xenopus contributes to cancer research

Cholangiocarcinoma in a red-tailed hawk (Buteo jamaicensis)

A review of neoplasia in the captive African hedgehog (Atelerix albiventris). Semin. Avian Exot

Green turtle fibropapillomatosis: challenges to assessing the role of environmental cofactors

Neoplasia of reptiles with an emphasis on lizards

Cutaneous epitheliotropic T-cell lymphoma with metastases in a Virginia opossum

Squamous cell carcinoma with hepatic metastasis in a saltwater crocodile

Neoplasia in free-flying ruffed grouse (Bonasa umbellus)

Neoplasia in zoo animals

Lymphoma in reindeer (Rangifer tarandus tarandus L.)

Tumours in free-living wild mammals and birds in Great Britain

Factors affecting the intensity of epidermal papillomatosis in populations of roach, Rutilus rutilus (L.), estimated as scale coverage

Animal models of melanoma

Pathology of Australian Native Wildlife

Epidemiology of neoplasia in captive black-footed ferrets (Mustela nigripes), 1986-1996

Neoplasia of captive yellow sea horses (Hippocampus kuda) and weedy sea dragons

Cancer selection

Endometrial adenocarcinoma in a Bengal tiger (Panthera tigris bengalensis) implanted with melengestrol acetate

Frequency and types of tumors in mammals and birds of the Philadelphia Zoological Garden

First description of malignant retrobulbar and intracranial teratoma in a lesser kestrel

Reptile Medicine and Surgery

Conservation biology: restoration of an inbred adder population

Inbreeding depression in an isolated population of adders Vipera berus

Novel genes continue to enhance population growth in adders (Vipera berus)

Field and laboratory studies of the etiology of liver neoplasms in marine fish from Puget Sound

Prevalence and body distribution of sarcoids in South African Cape mountain zebra (Equus zebra zebra)

Treatment of equine sarcoid in seven Cape mountain zebra (Equus zebra zebra)

A transitional cell carcinoma with squamous differentiation in a pericloacal mass in a sugar glider (Petaurus breviceps)

Cancer in wildlife, a case study: beluga from the St. Lawrence estuary

Incidence of pigmented skin tumors in a population of wild Montseny brook newt (Calotriton arnoldi)

Polycystic kidney and renal cell carcinoma in Japanese and Chinese toad hybrids

Wildlife cancer: a conservation perspective

Cholangiocarcinoma in a Margay (Felis wiedii)

Incidence and histology of renale tumors of leopard frogs from the north central states

Continued diminished prevalence of the Lucke renal adenocarcinoma in Minnesota leopard frogs

Cancer incidence in pet dogs: findings of the animal tumor registry of

Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams

Spontaneous proliferative lesions and tumors of the uterus of captive African hedgehogs (Atelerix albiventris)

Metastatic hepatocellular carcinoma in ocelot (Leopardus pardalis)

Diseases of king crabs and other anomalies

Diseases of captive cheetahs (Acinonyx jubatus jubatus) in South Africa: a 20-year retrospective survey

Uterine leiomyomas in three captive eastern bongo (Tragelaphus eurycerus isaaci)

Marine mammal neoplasia: a review

A case of melanoma in a native Australian murid, the spinifex hopping-mouse (Notomys alexis). Aust. Mammal

Type C virus in lymphosarcoma in northern pike (Esox lucius)

Comparative histopathology of gonadal neoplasms in marine bivalve mollusks

Multiple Neoplasia in a jaguar (Panthera onca)

A case report of hepatocellular carcinoma and focal nodular hyperplasia with a myelolipoma in two chimpanzees and a review of spontaneous hepatobiliary tumors in non-human primates

Incidence and nature of tumors in captive wild mammals and birds

Observations on naturally occurring neoplasms in birds in the state of Victoria

Krankheiten der Reptilien

First reports of proliferative lesions in the great white shark, Carcharodon carcharias L., and bronze whaler shark, Carcharhinus brachyurus Gunther

Xenopus, a unique comparative model to explore the role of certain heat shock proteins and non-classical MHC class Ib gene products in immune surveillance

Osteosarcoma of the maxilla with concurrent osteoma in a southern sea otter (Enhydra lutris nereis)

Tumorous growths of the tiger salamander, Ambystoma tigrinum, associated with treated sewage effluent

Neoplastic and possibly related skin lesions in neotenic tiger salamanders from a sewage lagoon

Inbreeding and risk of late onset complex disease

Multicentric neurofibromatosis with rectal prolapse in a California sea lion (Zalophus californianus)

Gallbladder adenocarcinomas in two captive African lions (Panthera leo)

Tumors of testis and midgut in aging flies

Multicentric lymphoma in a giant anteater (Myrmecophaga tridactyla)

Relationship between fibropapillomatosis and environmental quality: a case study with Chelonia mydas off Brazil

Sarcoid tumours in Cape mountain zebra (Equus zebra zebra) populations in South Africa: a review of associated epidemiology, virology and genetics

Comparative genetics of sarcoid tumouraffected and non-affected mountain zebra (Equus zebra) populations

A survey of diseases in captive red wolves

Naturally occurring neoplasms in pigeons in a research colony: a retrospective study

Neoplasms identified in free-flying birds

Primary lung cancers in birds and mammals of the Philadelphia Zoo

Diagnosis and treatment of a pharyngeal squamous cell carcinoma in a Madagascar ground boa (Boa madagascariensis)

Medical and surgical management of reproductive neoplasia in two western lowland gorillas (Gorilla gorilla gorilla)

Evidence of melanoma in wild marine fish populations

An epizootic of fibromatosis in gray squirrels (Sciurus carolinensis) in Florida

A retrospective study of tumours in blacktailed prairie dogs (Cynomys ludovicianus) submitted to a zoological pathology service

Uterine adenocarcinoma in a Przewalski's wild horse (Equus ferus przewalskii)

High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat

Pathology and epidemiology of ceruminous gland tumors among endangered Santa Catalina Island foxes (Urocyon littoralis catalinae) in the Channel Islands

Cancer: a missing link in ecosystem functioning?

Spontaneous uterine fibroleiomyoma in a captive cheetah

Chronic myelogenous leukemia in a great horned owl

Leiomyomas in two sea otters, Enhydra lutris

Prevalence, emergence, and factors associated with a viral papillomatosis and carcinomatosis syndrome in wild, reintroduced, and captive Western barred bandicoots (Perameles bougainville)

Cutaneous papillomatosis and carcinomatosis in the Western barred bandicoot (Perameles bougainville)

Relating tumor score to hematology in green turtles with fibropapillomatosis in Hawaii

Epizootiology of spirorchid infection in green turtles (Chelonia mydas) in Hawaii

Immune status of free-ranging green turtles with fibropapillomatosis from Hawaii

Feline cancer prevalence in South Africa (1998-2005): contrasts with the rest of the world

Myxomas in vesicular connective tissue Peters et al. (1994) Mytilus galloprovincialis Mediterranean mussel Gonadal neoplasia or germinoma Peters et al. (1994) ; Carballal et al. (2015) Mytilus trossulus Bay mussel Disseminated neoplasia of unknown origin Peters et al. (1994) ; Ciocan and Sunila (2005) Ostrea edulis European flat oyster Disseminated neoplasia of unknown origin Barber (2004) Tiostrea chilensis Dredge oyster Germinoma, hemic neoplasia Peters et al. (1994) 

We acknowledge the French zoological parks who welcomed us into their premises and provided data on their animals: Safari de Peaugres, Réserve