bovine papillomatosis

International Common Names

• English: bovine papillomatosis, warts in cattle; warts

Local Common Names

• UK: angleberries

bovine papillomavirus

Bovine papillomaviruses (BPVs) produce generally benign tumours of the skin and of the mucous membranes of the alimentary and urogenital tracts. The tumours, which may be papillomas or fibropapillomas, are commonly called warts and have been known for a long time, probably for centuries.

There are several distinct types of BPV which differ in the sites they infect and the type of lesion they produce. The six that have been characterised to date are as follows:

• BPV-1 produces fibropapillomas in the skin (including the skin of teats) and in the genital mucosa (Lancaster and Olson, 1978; Jarrett et al., 1980).

• BPV-2 produces fibropapillomas in the skin (Lancaster and Olson, 1978), in the mucosa of the alimentary tract (Jarrett et al., 1984a) and also tumours of the bladder mucosa (Campo et al., 1992).

• BPV-3 produces papillomas in the skin (Pfister et al., 1979).

• BPV-4 produces papillomas in the alimentary tract (Campo et al., 1980).

• BPV-5 produces small ‘rice-grain’ fibropapillomas on the udder and teats (Campo et al., 1981).

• BPV-6 produces papillomas on the teats (Jarrett et al., 1984b).

BPV-4 and BPV-5 have also each been identified in cutaneous papillomas on the head, suggesting that site specificity of these viruses may not be absolute (Bloch et al., 1994; 1996). It is likely that there are also other types of BPV that have not yet been characterised (Spradbrow et al., 1983; Samuel et al., 1985).

The tumours can be a considerable nuisance to animals and their owners. They may grow to a large size and impair function or be infested with fly larvae. They usually regress spontaneously after months or years but in animals grazing bracken fern, tumours in the alimentary tract or bladder may become malignant and so lead to death (Jarrett et al., 1978a; Campo, 1997). Papillomaviruses or their DNA have also been found in papillomatous lesions that are precursors to squamous cell carcinomas of the eye and skin in cattle (Ford et al., 1982; Spradbrow et al., 1987). It is uncertain whether papillomaviruses play a role in the development of these cancers.

digestive diseases of large ruminants
mammary gland diseases of large ruminants
reproductive diseases of large ruminants
skin and ocular diseases of large ruminants
urinary tract and renal diseases of large ruminants

Except in the case of malignant conversion, disease due to bovine papillomaviruses (BPVs) is seldom fatal. Some animals may be killed because of persistent lesions or ill thrift, but in most cases BPV-induced lesions are incidental findings at post-mortem examination.

Fibropapillomas due to BPV-1 and 2 may be found anywhere on the outside of the body. They are generally most numerous on the head, including around the mouth, eyes and ears (Pearson et al., 1958), and on the neck, shoulders and brisket, but they also occur on the thorax, abdomen, back, legs and on the anal and genital mucosa (Olson, 1990). Early lesions are pink, fleshy and hairless, with filiform projections on the surface, whereas mature lesions have dark, hard, keratinized surfaces (Studdert et al., 1988). The lesions may be sessile or pedunculated, and range from less than 1 cm in diameter to large lesions, often described as resembling cauliflowers, up to 10 cm. The surfaces may crack and bleed, and the tumours may contain pockets of pus or insect maggots (duCasse, 1961). Tumours on the genital mucosa have similar forms but a less horny surface (Olson, 1990). On the skin of the teats, BPV-1 produces fibropapillomas with multiple filiform projections (Lindholm et al., 1984).

Cutaneous papillomas occur on haired skin all over the body. They differ from fibropapillomas in being always sessile-flat or domed and in having fine fronds on the surface, often with hair growing between the fronds (Barthold et al., 1974). They are circular and up to a few centimetres in size, but may coalesce to cover large areas. BPV-3 was identified from cutaneous papillomas from one animal in Australia (Pfister et al., 1979), but it is not known whether it is the cause of all such lesions. Interdigital papillomas occur in dairy cattle but no virus has been demonstrated in them (Rebhun et al., 1980) and it is possible they have a different aetiology (Britt et al., 1996).

In the upper alimentary tract, sessile papillomas are found on the mucosa of the palate, tongue, cheek, oesophagus and rumen (Jarrett et al., 1978b; 1984a). They are typically caused by BPV-4, although evidence for other BPV types has been found in an Australian survey (Samuel et al., 1985). They are up to 1 cm in diameter and up to 2 cm high, with a roughened or fronded surface (Thorsen et al., 1974; Hamada et al., 1989). In cattle grazing bracken fern they may become very numerous, coalesce into large clumps or transform into squamous cell carcinomas (Campo, 1997).

Fibropapillomas associated with BPV-2 are usually restricted to the oesophagus and rumen (Jarrett et al. 1984a), although one has been found on the caudodorsal aspect of the tongue (Bloch and Vanselow, University of New England, New South Wales, Australia, personal communication, 2000), and Head (1976) states that fibropapillomas occur anywhere from the lips to the fore-stomachs. They are smooth and pearly white, ranging in size from 1 mm to 20 cm, and may be multilobular and pedunculated (Jarrett et al., 1984a; Gordon, 1997). They do not undergo malignant transformation, but may interfere mechanically with the digestive process; tumours on the tongue have been known to cause death by asphyxiation. On the teats, in addition to the fronded fibropapillomas caused by BPV-1, lesions may be produced by BPV-5 or 6. The former are small white "rice-grain" fibropapillomas; the latter are papillomas with a fronded surface. All three types can occur on the one udder (Lindholm et al., 1984).

Histologically, lesions induced by BPVs are characterised by acanthosis: thickening of the stratum spinosum, often in a papilliform pattern. Cells in the upper part of this layer and in the stratum granulosum show vacuolation around the nucleus, known as koilocytosis, and often contain numerous keratohyaline granules. There is usually accompanying hyper- and/or para-keratosis, which may extend into long fronds. In true papillomas, fine strands of dermal stroma may support the folded epithelium but there is no dermal proliferation. In fibropapillomas dermal fibroblasts proliferate in whorls and bundles to provide a dense core to the tumour, with epidermal rete pegs growing down into it.

There is some variation in histological appearance depending on the BPV type and the site of the lesion. Lesions may ulcerate, leading to a predominantly neutrophilic inflammatory reaction. This is distinct from the inflammatory infiltration seen in regressing lesions, which is mainly mononuclear (Jarrett et al., 1991). Lesions induced in the bladder by BPV-2 include haemangiomas (Campo et al., 1992), fibromas and polypoid growths involving epithelial hyperplasia and metaplasia (Brobst and Olson, 1965).

Proliferate lesions due to bovine papillomavirus (BPV) 1 or 2 may be detectable as early as 4 weeks after experimental inoculation of the skin (Lee and Olson, 1968; Jarrett et al., 1990a). They continue growing for some weeks, 10 to 17 weeks in one trial (Olson and Skidmore, 1959), and new lesions may appear especially at the sites of minor cutaneous injuries. There is considerable variation between individuals in the number and size of lesions that develop and in the time course of the disease (Olson et al., 1960; 1992). The incubation period may be longer in the case of natural infections, although warts have been seen on one-month-old calves (Olson et al., 1960). Recorded periods between procedures thought to spread the infection and appearance of lesions have ranged from less than two (Studdert et al., 1988) to more than 4 months (Tweddle and White, 1977). Experimental inoculations with BPV 4 or 6 have also resulted in detectable lesions within 4 weeks, whereas with BPV-5 papillomas were not seen until 26 weeks (Jarrett et al., 1990b).

Cutaneous and anogenital fibropapillomas usually regress spontaneously after periods ranging from a month to well over a year (Brobst and Olson, 1965; Lee and Olson, 1968). Regressing lesions become dry and shrunken, and the animals may rub at them as if they are pruritic. Usually all lesions regress simultaneously, without leaving scars. Experimentally induced lesions of BPV-4, 5 and 6 may take more than a year to regress (Jarrett et al., 1990b). Papillomas due to BPV-3 have been little studied, but similar, so-called ‘atypical’, cutaneous papillomas in America have been observed to persist for long periods, up to 4 years in some animals (Barthold et al., 1974).

Regression is accompanied by infiltration of the lesions by T-lymphocytes, and is believed to be due to specific cell-mediated immunity (Campo, 1997). Animals bearing papillomas due to more than one BPV type may lose one type of lesion while retaining others; for example, in calves with fibropapillomas and ‘atypical’ cutaneous papillomas, the fibropapillomas regressed while the true papillomas persisted (Barthold et al., 1974). Recovered animals have immunity to the causative BPV, but not to BPVs of other types (Jarrett et al., 1990b). This immunity to re-infection in fact develops while lesions are still present; it is humorally mediated and is not linked to regression (Lee and Olson, 1968; 1969; Campo, 1997).

In a small number of individuals, fibropapillomas persist for long periods and are refractory to treatment. The reason for this is not known, but in one such animal there was evidence for suppression of cellular immunity (Duncan et al., 1975). Kuchroo et al. (1983) demonstrated specific blocking factors in the serum of three cattle with BPV-3 papillomas. Non-specific immunosuppression of calves infected with BPV-4 resulted in unusually numerous alimentary papillomas which failed to regress, as well as production of bladder tumours by latent BPV-2 (Campo et al., 1992; Campo, 1997).

Papillomaviruses infect cells in the basal stratum of the epidermis, inducing hyperplasia. Bovine papillomaviruses (BPVs) one, two and five also infect fibroblasts in the underlying dermis. Viral replication is tied to cell differentiation, with mature virions appearing only in the outer epidermal layers and being shed in exfoliated cells (Pfister, 1984; Campo, 1997). No virions are produced in the infected dermal cells of fibropapillomas, but there are large amounts of virus in their keratinized outer covering.

It is assumed that susceptible animals become infected when they rub against an infected herd-mate, with the virus gaining entry through small abrasions. The virus persists for some time on structures such as posts and fences that animals rub against (Campo et al., 1994). It can also be spread by items used for grooming and handling animals, including human hands (Studdert et al., 1988). There are no known vectors,  although it has been suggested that biting flies may spread the virus mechanically (Du Casse, 1961). BPV-4, which induces lesions of the upper alimentary tract, may be spread in the saliva of animals.

There is evidence for latency of BPV-1 and 2. Calves born to mothers free of lesions, and raised from birth in isolation, developed fibropapillomas at sites of minor skin injury, or bladder tumours when they were immunosuppressed. DNA of BPV type 1 or 2 was found in the lesions and in peripheral blood lymphocytes (Campo et al., 1994).

The diseases caused by the bovine papillomaviruses (BPVs) are generally of minor economic importance, although they can be a cause of loss in individual animals and herds (Olson and Skidmore, 1959; Prasad et al., 1980). Cutaneous lesions reduce the value of hides, and may prevent sale or exhibition of animals (Studdert et al., 1988). Severely affected animals have retarded growth rates and suffer secondary infections (Pearson et al., 1958; Du Casse, 1961). Lesions on the genitalia, especially in bulls, interfere with mating (Pearson et al., 1958). Lesions on the teats present problems for milking (Olson et al., 1982; Lindholm et al., 1984) and occasionally lead to mastitis via secondary bacterial infection (Moussa et al., 1983). In areas where cattle are exposed to bracken fern, losses due to bladder tumours can be significant (Pamukcu, 1963).

The genomes of bovine papillomavirus (BPV) 1 and 2 have some homology with that of human papillomavirus type 1 (Lancaster and Olson, 1982; Coggins et al., 1983). Despite this, and despite their ability to infect a number of species, they have failed to transform human cells in vitro. A high prevalence of warts among butchers and abattoir workers has led to the belief that these are caused by infections from cattle; however, investigations of these warts have failed to detect any of the known BPVs (Pfister, 1984). Meischke (1979b) demonstrated infective BPV in pasteurised milk, but there are no reports of human infections attributed to milk.

Most BPV-induced lesions occur on parts of the animal that are not used for human consumption. Papillomas on edible parts of the alimentary tract, such as the tongue, would normally be trimmed away for aesthetic reasons.

In most cases the best course of action is to wait for lesions to regress spontaneously. Individual warts that are troublesome may require removal.

Pedunculated fibropapillomas can often be pulled off with little bleeding or evidence of pain. Alternatively, they can be removed surgically, or ligated. Surgical removal of sessile lesions from the teat or penis can result in undesirable scarring (Olson, 1990). There are claims that removal of one or two warts can result in regression of all the remaining lesions (Belschner and Edwards, 1984), but in some trials excision has appeared to stimulate further growth of lesions (Olson and Skidmore, 1959; Du Casse, 1961). Surgery should therefore be approached with caution, particularly early in the course of the disease. Cryosurgery and electrocautery have also been used but are probably attended by the same hazards.

A large number of substances have been recommended for treatment of papillomatosis, but because the lesions regress spontaneously and unpredictably it has been hard to assess their efficacy. Du Casse (1961) found systemic administration of bismuth, calcium sulphide or arsenic ineffective as well as difficult and dangerous. Du Casse (1961) and Prasad et al. (1980) found little effect of systemic lithium antimony thiomalate (anthiomaline), although Wadhwa et al. (1996) reported over 50% efficacy for it. The potential for toxicity and residues make its use inadvisable. Bovine interferon has been used but treated warts grew faster than controls (Lassauzet and Salamin, 1993).

Suggested topical applications have included castor or olive oils, copper sulphate, caustic potash, salicylic or glacial acetic acids (Belschner and Edwards, 1984) and dimethyl sulphoxide (Donovan, 1983). However, there has been little evidence offered of their efficacy. No response has been found to tincture of iodine (Amin et al., 1997) and Du Casse (1961) reported a slight response to formalin and good results with podophyllin ointment. Various plants that have caustic or irritant sap have also been used. With all such substances it is necessary to protect the surrounding skin with petroleum jelly; application is therefore time-consuming but may be worthwhile for single troublesome papillomas.

The most consistently recommended treatment has been vaccination with homogenates of lesion tissue. Several workers observed regression of lesions after this treatment (Pearson et al., 1958; Du Casse, 1961; Prasad et al., 1980) although others did not (Olson and Skidmore, 1959). Recent experiments have shown that vaccination with sub-units of bovine papillomavirus (BPV) does induce regression of lesions caused by that BPV type (Jarrett et al., 1991; Campo et al., 1993). Earlier variable results may have been due to vaccines being prepared from lesions of a different BPV type, from lesions that were not producing virus, or from the fibromatous core of the lesion. In the future, effective sub-unit vaccines may be available.