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Multiple canine papillomas in dogs are uncommon, comprising less than 12.5% of canine skin tumors. Papillaviruses of humans, cattle, horses, dogs, and cats share at least one group-specific determinant. Canine oral papilomavirus (COPV) into kittens, mice, rats, guinea pigs, rabbits, and nonhuman primates has failed to produce papillosis.
Multiple canine papillomas in dogs are uncommon, comprising less than 12.5% of canine skin tumors. Papillaviruses of humans, cattle, horses, dogs, and cats share at least one group-specific determinant. Canine oral papilomavirus (COPV) into kittens, mice, rats, guinea pigs, rabbits, and nonhuman primates has failed to produce papillosis.
Multiple canine papillomas in dogs are uncommon, comprising less than 12.5% of canine skin tumors. Papillaviruses of humans, cattle, horses, dogs, and cats share at least one group-specific determinant. Canine oral papilomavirus (COPV) into kittens, mice, rats, guinea pigs, rabbits, and nonhuman primates has failed to produce papillosis.
Infectious Diseases of the Dog and Cat, 3rd Edition
CHAPTER 9 Canine Viral Papillomatosis
Michelle Wall Clay A. Calvert ETIOLOGY The papillomavirus was first described in 1933 when Shope discovered the agent responsible for cutaneous papillomas in the cottontail rabbit. 19 Multiple canine papillomas in dogs are uncommon, comprising less than 12.5% of canine skin tumors. 20 Benign mucocutaneous tumors of epithelial origin are caused by infectious papillomavirus of the Papovaviridae family. The papilloma viruses are categorized with the polyomaviruses to form the papovaviruses. Members of this family are small (33 to 60 nm), naked, ether-resistant, double-stranded circular DNA tumor viruses, similar in structure to but larger than parvoviruses; they form crystalline structures within the nuclei of infected cells. 22,34 These viruses lack a lipid envelope and are acid stable and relatively thermostable, which may explain much of their inherent resistance. 34 Papillomaviruses are naturally oncogenic, producing benign warts, and are usually species and site specific. Cross-species infection of horses by bovine papillomaviruses type 1 and type 2 have been reported. 13 Most isolated viruses lack serologic cross-reactivity. Although antigenically distinct, papillomaviruses of humans, cattle, horses, dogs, and cats share at least one group-specific determinant. Inoculation of canine oral papillomavirus (COPV) into kittens, mice, rats, guinea pigs, rabbits, and nonhuman primates has failed to produce papillomas. Tumors can be transmitted experimentally within the species of origin by scarification with whole cells or cell-free filtrates. A distinct papillomavirus has been identified in cutaneous papillomas of cats (see Chapter 20) and dogs. 26,41 The close genetic relationship between feline and canine papillomas compared with those of other species supports the hypothesis that papillomaviruses have coevolved with vertebrates during host evolution. 49,52 EPIDEMIOLOGY Papillomas (also referred to as warts, verruca vulgaris squamous cell papillomas, or cutaneous papillomatosis) may be either (1) naturally occurring noninfectious or virus-induced solitary tumors or (2) transmissible virus-induced multiple tumors. The virus is transmitted by direct and indirect contact, but damaged epithelial surfaces may be necessary for successful inoculation. 3,16 The papillomavirus must overcome the host's immune response to replicate and produce clinical infection, so the significance of these warts is greater in immunocompromised patients. 13,34
Four or more separate papillomaviruses may infect dogs, usually without papilloma development. Numerous clinical syndromes and symptoms have been described in dogs with papillomavirus: oral papillomatosis, venereal papillomas, cutaneous papillomas, cutaneous inverted papillomas, multiple papillomas of the footpad, and papillomavirus-associated canine-pigmented plaques. Most infectious papillomas undergo spontaneous regression, but occasionally papillomavirus infections persist or lesions recur, especially when the host is immunocompromised and the immune system cannot eliminate the virus (e.g., in a dog with concurrent infections). Dogs with granulocytic ehrlichiosis had remission of oral papillomatosis after treatment. 50 Malignant transformation into squamous cell carcinoma has been reported in various species, especially cattle. Progression to sarcoid tumors has also been reported in horses, donkeys, and mules as a result of bovine papillomavirus infection. 18 74 9 9.1 9.2 CHAPTER 9 Canine Viral Papillomatosis Page 1 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition The association of human papillomavirus and bladder cancer remains unresolved, 24,37 but strong evidence supports the role of human papillomavirus in cancer of the anogenital tract. 22 The human papillomavirus is a critical factor in the development of cervical cancer. 4 Progression of the papillomavirus to carcinoma can occur in dogs, although malignant transformation is uncommon. Reports have been made of a beagle with oral papillomatosis and a collie with an oral and a corneal papilloma that experienced malignant transformation. 1,54 The interaction of certain chemicals, genetic background, or other carcinogens with papillomavirus-infected cells is believed to produce the potential for malignant transformation; for example, human laryngeal papillomas exposed to irradiation and bladder tumors in cattle exposed to bracken fern create the potential for transformation. 8,13 PATHOGENESIS The life cycle of the papillomavirus is closely associated with the differentiating epithelial cell, and infections with papillomavirus are usually confined to the epidermis and epithelium. 39 Papillomavirus infects basal keratinocytes of the stratum germinativum; the basal cell is the only cell in the squamous epithelium that is capable of undergoing division. 55 Once it has infected the basal layer, the virus expresses itself in the basal and suprabasal layers, undergoes genome replication in the granular and spinous layers, packages its DNA in the squamous layers, and releases a new infectious virus with the keratinized squames. 13 The first tissue response to COPV infection is an increase in mitotic activity, resulting in acanthosis and hyperkeratosis. As the disease progresses, some infected cells begin producing virus. These cells develop inclusion material but do not undergo cytoplasmic differentiation. Cytoplasmic degeneration and cell death ensue with viral persistence in strands of keratin; however, the majority of basal layer cells differentiate into keratogenetic normal cells. Spontaneous tumor regression is the usual course. The virus is latent in the basal layers, although complete viral particles may be identified at the granular level. The incubation period of COPV is usually 4 to 8 weeks postinoculation. Concentration of COPV in the inoculum may influence subsequent tumor growth and regression in various ways. Papillomavirus infection delays the activation of the host's immune system. The virus targets end-stage differentiating cells and is often protected from systemic immune defenses, and the production of papillomavirus is not accompanied by inflammation. 34 Dogs given small doses of virus develop more papillomas and have delayed regression compared with dogs given larger doses of virus. Antibodies to papillomavirus are produced, but they do not correlate with growth or regression. Once regression occurs, subsequent immunity develops. The mechanisms resulting in spontaneous regression or spread of papillomas are unknown. Papilloma regression is thought to be associated with the presence of CD4 + and CD8 + lymphocytes. These cells, especially the CD4 + cells, activate macrophages, inhibit viruses via cytokines, kill keratinocytes, or all of these. 34 Virus-neutralizing antibody inactivates COPV in sensitized animals but does not inhibit established virus or papillomas. Serum from dogs whose papillomas have undergone spontaneous regression usually not only fails to produce tumor regression but also can enhance tumor growth in naive dogs. Passive transfer of serum immunoglobulins from immune dogs may occasionally protect naive dogs. 34,48 Failure of protection by serum immunoglobulins from dogs that have undergone spontaneous regression may be the result of the induction of blocking antigen-antibody factors that impede cytotoxic lymphocyte action on target cells. Severe oral papillomatosis occurs in beagles with IgA deficiency. 47 Cellular immune mechanisms may be more important in inhibiting the development of early papillomas in dogs. Regression is enhanced by the injection of immune lymphocytes from dogs in which COPV has regressed. In contrast, COPV papillomatosis spread from the oral cavity throughout the haired skin of a Shar-pei dog given glucocorticoids. 47 Multiple cutaneous papillomas caused by a new papillomavirus developed in a boxer 9.3 CHAPTER 9 Canine Viral Papillomatosis Page 2 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition dog receiving long-term glucocorticoid therapy, and similar associations were recognized in dogs with hypogammaglobulinemia, IgM deficiency, impaired T-cell responses, and high dose, long-term cyclosporine administration. 7,9,26,40 In humans, increased prevalence of papillomatosis is associated with defects in the cell-mediated or humoral immune system as well. Puppies inoculated with COPV develop hyperplastic and neoplastic lesions at sites other than the oropharyngeal mucosa. Lesions have included epidermal hyperplasia, epidermal cysts, squamous papilloma, basal cell epithelioma, and squamous cell carcinoma; however, very few inoculations were associated with these extraoral lesions. CLINICAL FINDINGS Oral papillomas occur on the oral, labial, and pharyngeal mucosa, as well as on the tongue, on the hard palate, and on the epiglottis; it rarely occurs in the esophagus (Fig. 9-1). Oral papillomatosis of young dogs (with a median age of 1 year) is a contagious viral disease. 27 The lesions typically begin as white, smooth, flat, shiny plaques that progress, usually 4 to 8 weeks postinfection, to pedunculated or cauliflower-like masses. 13,27 The oral form is usually a self-limiting disease, although the lesions may persist without spontaneous regression or spread to other areas of the body. 39 Fig 9-1 Typical canine oral papillomatosis in young dogs. A, Single labial papilloma. B, Papillomas on the tongue, hard palate, and labial surface. C, Multiple labial papillomas. D, Extensive oral papillomatosis. (Courtesy Patrick Hensel and Tracy Gieger, University of Georgia, Athens, Ga.) 74 75 9.4 CHAPTER 9 Canine Viral Papillomatosis Page 3 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition Ocular papillomas can occur on the conjunctivae, cornea, and eyelid margins (Fig. 9-2). Ocular papillomas are less common than oral papillomas and are caused by a virus that is similar in structure to the oral papillomavirus. Virus-induced cutaneous papillomas are uncommon and usually solitary lesions caused by a subtype of the canine papillomavirus; they are not associated with the papovavirus. Although usually solitary, the cutaneous lesions may be multifocal and are often found elsewhere on the body (Fig. 9-3). COPV inoculated into the skin of the face may produce a papilloma, but attempts to produce a tumor by inoculating the skin of the abdomen or back with COPV have usually failed. Dogs older than 2 years of age seldom develop oral papillomas, and older dogs appear to be resistant to COPV infection. Ocular papillomas occur most often in dogs 6 months to 4 years of age but have been reported in dogs as old as 9 years. The susceptible age range of dogs with cutaneous papillomas is broader. Cutaneous papillomas occur in older dogs and appear to be more common in males. 39 The Kerry blue terrier and the cocker spaniel have been reported to be overrepresented. 39,41 The cutaneous warts are distinct from the oral form and usually occur on the head, feet, and eyelids. In Australia, cutaneous papillomas of the distal limbs and interdigital pad area in racing greyhounds occur in dogs 12 to 18 months of age. 14 Cutaneous inverted papillomas usually occur on the ventrum and inguinal regions. 11 They have been reported to occur in dogs from 8 months to 7 years of age. 11,41 These small, firm, raised masses appear as cup-shape lesions with a central core of keratin that have a small pore opening to the skin surface. 27 Their surface is similar to that of an intracutaneous cornifying epithelioma, but they have a papillary projection of epidermis into the lumen that epitheliomas do not possess. 11 Single or multiple lesions may develop, and they are covered by skin with a central pore opening to the surface. Multiple papillomas affecting the footpads have been described in adult dogs. 39 The lesions are very firm and hyperkeratotic. They can occur on more than one foot and often cause lameness (Fig. 9-4). They do not seem to be associated with a virus. Papillomavirus-associated canine-pigmented plaques have been documented in several miniature schnauzers and pugs during young adulthood. 32 These lesions often progress over time and do not regress. Potential for malignant transformation exists. Although oral papillomatosis is the most common clinically relevant disease, other forms are recognized. Oral papillomatosis is a contagious, usually self-limiting disease affecting the oral mucosa, labial margins, tongue, palate, pharynx, and epiglottis. Initially, oral papillomas are pale, smooth, elevated lesions, but they soon become cauliflower-like, with fine, white, stringy projections. Early tumors appear to seed the rest of the susceptible oral tissues. Recognition of the lesions usually occurs while the numbers of tumors are still increasing. Halitosis, ptyalism, hemorrhage, and oral discomfort are clinical signs observed by the owners of affected dogs. These lesions often bleed when traumatized. As many as 50 to 100 tumors are often present at the time of diagnosis (see Fig. 9-1, C and D). Papillomavirus infections usually regress spontaneously, but the time to regression varies from weeks to years. Regression typically occurs within 4 to 8 weeks. Oral papillomas usually regress after 4 to 8 weeks, although they may persist for up to 24 months. Cutaneous papillomas may persist for 6 to 12 months before undergoing spontaneous regression. Occasionally, incomplete regression occurs, and a few papillomas persist indefinitely. Dogs 75 76 CHAPTER 9 Canine Viral Papillomatosis Page 4 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition affected by persistent papillomas often have many large tumors and may become malnourished. Secondary bacterial infection of large, persistent, and ulcerated tumors is common and characterized by a mucopurulent discharge. Fig 9-2 Eyelid papilloma in a dog. Fig 9-3 Multiple papillomas on the (A) lateral flank and (B) caudal thigh of two different dogs. (Courtesy Patrick Hensel, University of Georgia, Athens, Ga.) CHAPTER 9 Canine Viral Papillomatosis Page 5 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition Ocular papillomas tend to persist longer than oral papillomas and are usually less numerous. When COPV was inoculated into the eyelids of dogs, only 50% of the dogs developed papillomas, the incubation period was longer than it is in the oral cavity, and the tumors persisted longer than they do in the oral cavity. 53 Experimentally papillomavirus isolated from ocular lesions can produce oral papillomatosis, but it has not been proven that this occurs naturally. 27 DIAGNOSIS The diagnosis of papillomatosis is based on the epidemiology and gross appearance of the tumors. Ocular papillomas are usually biopsied and examined histologically because they are not as morphologically distinct as oral papillomas. Microscopic features of papillomas include marked epidermal hyperplasia on fibrovascular stalks. Small, intranuclear, basophilic inclusions may be noted and in some cases, keratinocytes within the papillomas may contain large eosinophilic cytoplasmic inclusions. 15 Cutaneous papillomas, usually morphologically distinct, are often excised for aesthetic reasons and examined microscopically. Cutaneous papillomas can occur at many sites, most often on the lower extremities, often in the interdigital areas and footpads, and occasionally subungually. The viral cause can be confirmed by immunohistochemistry staining for viral antigen, electron microscopy findings demonstrating the virus, or polymerase chain reaction and in situ hybridization techniques to detect papillomavirus DNA. * Fig 9-4 Footpad papilloma in a young dog. A, Papilloma near the metacarpal pad. B, Papilloma at the nail bed. (Courtesy Patrick Hensel, University of Georgia, Athens, Ga.) * References 7,15,39,42,47,51. THERAPY Treatment is not indicated if only a few papillomas are present because they are usually self-limiting, and afterward dogs are immune to reinfection. 39 However, the patient should be frequently monitored to determine whether the tumor numbers are increasing. Spontaneous regression is the usual course, but treatment may be indicated when tumors persist; when large, multiple tumors produce pharyngeal obstruction; when problems eating occur; and for 76 77 9.5 9.6 CHAPTER 9 Canine Viral Papillomatosis Page 6 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition aesthetic reasons. Treatment efficacy is often difficult to determine because of the high incidence of spontaneous regression. The ideal therapy remains unknown because of the lack of sufficient knowledge regarding papillomavirus. Surgical excision, cryosurgery, and electrosurgery are acceptable modes of oral tumor treatment. Surgical removal, freezing, or simply crushing 5 to 15 of the tumors may induce spontaneous regression, presumably a result of antigenic stimulation. Laser therapy has been effective in the treatment of several resistant human warts and has been described for human recurrent respiratory papillomatosis. 17 Oral papillomatosis has been unsuccessfully treated with a CO2 laser. 25 Although autogenous vaccines are commonly recommended, their efficacy in dogs is questionable, and they are often not effective against persistent papillomatosis. Recombinant vaccines have been shown to induce regression in several species including the dog and can be used prophylactically to prevent mucosal infections with COPV. 3,23,25,47 It has been demonstrated that systemic immunization with COPV L1 protein can induce a humoral response that will provide protection against oral papillomatosis. 48 The vaccines may also play a role in decreasing the development of squamous cell carcinomas. In a case report of a 16-month-old Siberian husky that did not respond to surgical therapy, an autogenous vaccine appeared to induce regression of the resistant oral papillomas, and high circulating neutralizing antibodies against COPV were produced. 25 The titers appeared to be correlated with regression of the oral papillomas. 25 Anecdotal reports have been made of success with the use of autogenous vaccines. Additional studies should be performed regarding the effectiveness of recombinant COPV vaccines because the development of neoplasms has been reported to occur at the injection site of live COPV vaccines in dogs. 8,28,45 Cutaneous papillomas that arise as a result of glucocorticoid-induced immunosuppression may regress once this therapy is discontinued. Surgical excision or cryosurgery is effective for papillomas of the conjunctiva or eyelid. Cryosurgery is not recommended for corneal papillomas. Care should be taken to prevent spread of the virus to adjacent ocular tissues, and cryosurgery or possibly laser therapy may offer an advantage in this regard. Systemic and intralesional (bleomycin) chemotherapy using single-agent vincristine, cyclophosphamide, or doxorubicin has been ineffective in the majority of dogs treated. Topical application of 5-fluorouracil (0.5% solution) has been used successfully in humans with numerous cutaneous warts, a treatment that may be useful for cutaneous lesions in dogs. However, ingestion of 5-fluorouracil can result in local irritation and severe systemic toxicity. The retinoid etretinate has been useful in the treatment of a few dogs with cutaneous papillomatosis. Widespread papillomavirus-associated canine-pigmented plaques have been effectively treated with etretinate (1 mg/kg orally every 24 hours). 32,33 Possible retinoid toxicity can include conjunctivitis, pruritis, vomiting, diarrhea, joint stiffness, pedal and mucocutaneous erythema, hyperactivity, and teratogenicity. Interferons (IFNs) have been administered parenterally and intralesionally to affected humans until regression occurs. Low doses of oral IFNs rather than high doses of parenteral IFNs are more commonly used in pets and less expensive, but not likely to be effective. In vitro studies of IFN therapy have shown a reduction in the papillomavirus in mouse cells transformed by bovine papillomavirus-1. 32 The immune modulator Acemannan (Acemman Immunostimulant, Carrington Labs, Irving, Tex.) has been administered intralesionally to cause regression of fibrosarcomas and might be an alternative to IFN therapy. Photodynamic therapy has induced good responses for several types of skin cancer and may play a role in future treatment of canine papillomas. Dogs recovering from oral papillomatosis are immune, as are most dogs older than 2 years (see Interferons, Chapters 2 and 100; Acemannan, Chapter 100; and Drug Formulary, Appendix 8 for additional information on administration and precautions of these drugs). 77 78 CHAPTER 9 Canine Viral Papillomatosis Page 7 of 8 Infectious Diseases of the Dog and Cat, 3rd Edition PREVENTION Protection against viral challenge with COPV has been achieved by sequential immunization doses via DNA delivery of a plasmid encoding COPV major capsid L1 protein or oncoproteins E1 or E2 to cutaneous and oral mucosal sites in beagles. 31,43,44 Codon-optimized E1 gene sequences (but not wild-type gene sequences) provided complete protection after DNA vaccination of beagle dogs with COPV. 31 Both cell-mediated and humoral immune responses were detected. No vaccine is commercially available. Suggested Readings * * See the CD-ROM for a complete list of references. 31. Moore, RA, Walcott, S, White, KL, et al.: Therapeutic immunization with COPV early genes by epithelial DNA delivery. Virology. 314, 2003, 630635. 32. Nagata, M: Canine papillomatosis. In Bonagura, JD (Ed.): Kirk's current veterinary therapy XIII. 2000, WB Saunders, Philadelphia, PA, 569571. Uncited references 12. Campo, MS: Animal models of papillomavirus pathogenesis. Virus Res. 89, 2002, 249261. 36. Nicholls, PK, Stanley, MA: Canine papillomavirusa centenary review. J Comp Pathol. 120, 1999, 219233. 9.7 9.8 9.9 CHAPTER 9 Canine Viral Papillomatosis Page 8 of 8
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