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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
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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
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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.)
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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
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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
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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
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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).
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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.
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