Page 41 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

20 PART I The Biology and Pathogenesis of Cancer

the polymerase chain reaction (PCR) most often is used to detect
the virus in tissues. 403 Detection of the P16 protein in tissues by
immunohistochemistry often is used to link papilloma infection
VetBooks.ir to neoplastic transformation. 404,405 As are other papillomaviruses,
canine papillomaviruses are resistant, acid stable, and relatively
thermostable. 283 Only limited sequence homology exists between
the DNA sequences of papillomaviruses of different species, but
substantial sequence homology exists between isolates from any
given species. Canine isolates have preferential tissue tropisms, but
these tropisms have been shown to broaden with glucocorticoids
and other immunosuppressive therapies. 403

Pathogenesis
Papillomaviruses have a tropism for squamous epithelial tissues.
After the introduction of the papillomavirus through breaks in the
surface of the epithelium, replication of the virus is linked to the
growth and differentiation of the cells in the stratified squamous
epithelium. After the virus enters the basal layer keratinocytes, • Fig. 1.9 Multiple papillomatosis in the oral cavity of the dog.
the virus undergoes disassembly and early (E) protein enters the
nucleus and produces episomal copies of viral DNA. The ability
of the papillomavirus to express the E gene forces the infected
cell to divide, thus maintaining viral replication. 403 As these cells
progress to the surface, they express the late gene (L), which forms
the capsids of the virus, which then are released in the sloughing
epithelial surfaces. A key feature of papillomaviruses in tumori-
genesis is the E proteins, which prevent infected cells from leaving
the cell cycle and are classified as oncoproteins. The amount of E
protein produced and the interactions of these proteins with cellu-
lar regulatory systems, including p53, is believed to be responsible
for lesion production and tumor risk. 403
The tissue tropism for papillomaviruses may be expanded in
immunosuppressed patients. The type of papillomavirus and the
host’s immune response after inoculation predict the risk for clinical
disease; a good host response provides protection from the devel-
opment of clinical disease, in which case the infection remains
asymptomatic. 404,408 The presence and location of mature complete • Fig. 1.10 Solitary ocular papilloma in a dog.
viruses on the surface of papillomas are believed to aid in their trans-
mission to adjacent epithelial tissues and often are believed to be the young dogs. In the dog multiple papillomatosis most frequently is
cause of surgical treatment failure. 278 In contrast to other oncogenic seen in the oral cavity, involving the labial margins, tongue, pha-
or transforming DNA viruses, papillomaviruses rarely integrate into ryngeal mucosa, hard palate, and epiglottis (Fig. 1.9). 287 Four to 8
the cellular genome and remain episomal. 278 weeks after infection, small, pale, smooth, elevated lesions appear;
Infection of epithelial cells results in a marked increase in cellu- these quickly develop a cauliflower-like appearance, with fine,
lar mitosis and hyperplasia of cells within the stratum spongiosum, white fronds extending from the surface of the lesions. Multiple
286
with subsequent degeneration and hyperkeratinization. Clinical sites of susceptible tissue in the oral cavity appear to be affected
evidence of hyperplasia and hyperkeratinization usually manifests 4 early in the course of the disease; as many as 50 to 100 tumors may
286
to 6 weeks after experimental infection. Canine papillomas gener- be present at the time of diagnosis. 287 The primary complaints of
ally persist for 4 to 6 months in the mouth and 6 months to 1 year owners of infected dogs are halitosis, ptyalism, hemorrhage, and
on the skin before undergoing spontaneous regression, and multiple dysphagia. Most oral cavity papillomas start regressing after 4 to
286
papillomas generally regress simultaneously. Although antibod- 8 weeks; however, some oral lesions may show incomplete regres-
ies are produced against the papillomavirus, antibody levels do not sion, and some have been known to persist up to 24 months. 287,406
appear to correlate with either growth or regression of the papilloma Canine cutaneous (exophytic) papillomas are most commonly
during infection; the mechanism of induction or regression remains found in older dogs. Certain breeds, such as Kerry blue terriers
unknown. Although vaccination has been shown to protect against and cocker spaniels, appear to be predisposed. Most lesions appear
infection, it is thought to be associated with induction of cell-medi- on the head, eyelids (Fig. 1.10), and feet. Lesions may be single or
ated immunity. The development of multiple papillomavirus-asso- multiple, pigmented and/or alopecic.
287
ciated epidermal lesions and SCC in situ in a dog after treatment with Cutaneous inverted papillomas are found most frequently in
prednisone and cyclosporine has been reported. 288,409 young dogs and are located on the ventral abdomen and inguinal
regions. The lesions maybe single or multiple and are considered
Clinical Features self-limiting (Fig. 1.11). 406
Papillomas may be referred to as warts, verruca vulgaris, squamous Multiple pigmented plaques have been described in young
cell papillomas, or cutaneous papillomatosis. Papillomas caused miniature schnauzers and pugs. The plaques may progress to scaly,
by the papillomavirus usually are multiple and frequently involve hyperkeratotic flat masses and then may progress to SCC. 289,406