Successful treatment of florid papillomatosis in a dog using

TREATMENT OF FLORID PAPILLOMATOSIS IN A DOG
25
Successful treatment of florid papillomatosis in a dog
using subcutaneous feline recombinant interferon-ω
O. FANTINI, E. VIDEMONT, D. PIN*
Dermatology–Dermatopathology Unit, VetAgro Sup Veterinary Campus Lyon, 1 Avenue Claude Bourgelat, Marcy l’Etoile, 69280 - France
* Corresponding author: [email protected]
ABSTRACT
RÉSUMÉ
An eight-month-old Pug dog was presented for treatment-resistant
disseminated exophytic papillomatosis affecting the oral mucosa, and
the haired skin. Two courses of recombinant feline interferon-ω given by
subcutaneous injection once daily for 5 consecutive days at two-week
intervals, allowed a complete regression of papillomatosis with no adverse
effects.
Un cas de traitement de papillomatose chez un chien par administration
sous-cutanée d’interféron ω félin recombinant.
Keywords: Dog, papillomavirus, oral and cutaneous
papillomatosis, feline recombinant interferon-ω.
Un chien Carlin âgé de 8 mois est atteint d’une papillomatose généralisée,
affectant le corps et la cavité orale et réfractaire aux différents traitements
mis en œuvre antérieurement. Deux séries d’injections sous-cutanées
d’interféron-ω recombinant d’origine féline de 5 jours consécutifs, ont
permis une régression totale de toutes les lésions sans effet secondaire.
Mots-clés : Chien, papillomavirus, papillomatose orale et
cutanée, interféron-ω recombinant d’origine féline
Introduction
Case report
The papillomaviruses (PV) are a large group of speciesspecific, small nonenveloped double-stranded DNA viruses
that have a tropism for the skin and for mucosal membranes,
and are associated with various hyperplastic, dysplastic and
neoplastic conditions in humans and animals [13].
An 8-month-old male Pug dog was referred with alopecia,
erythematous suppurative dermatitis, and disseminated
cauliflower like exophytic warts affecting the oral mucosa, face
and appendicular haired skin, appeared 3 months before. Two
other dogs in the household were reported to show the same
lesions with spontaneous resolution. Treatment prior to
referral included a six-week course of twice weekly 0.5ml/kg
intravenous magnesium chloride, daily topical application of
Thuja occidentalis, a 10-day-course of daily oral spiramycin
and metronidazole (Stomorgyl; Merial), and a 30-day-course
of 10mg/kg once daily oral azithromycin (Zitromax; Pfizer).
Fifteen papillomaviruses have been cloned from and
appear to be associated with certain clinical lesions in the dog.
In this species, papillomatosis is, in general, a self-limiting
disease, requiring no treatment. However, persistent lesions
may be associated with defective cell-mediated immunity
and treatment may be necessary [33].
Various treatment of papillomatosis in dogs have
been described: oral azithromycin [33], cimetidine [6],
etretinate [22] and human recombinant interferon-α 2a [27],
intramuscular Propionibacterium acnes [21], intravenous
taurolidine [3], subcutaneous live papillomavirus vaccine
[4], topical applications of 5-fluorouracil or imiquimod and
surgical excision, crushing laser surgery or cryosurgical
intervention [22]. However, no single treatment has
been shown to be superior. Topical application and/or
subcutaneous injection of Thuja occidentalis has been used,
in human, dog and cattle, to treat verruca vulgaris [14],
canine oral papillomatosis [19] and cutaneous papilloma
[31]. Intravenous magnesium chloride has been reported to
be effective in bovine cutaneous papillomatosis [11].
This report describes the clinical and histopathological
features of a severe refractory case of oral and cutaneous
papillomatosis in a dog successfully treated by subcutaneous
injections of rFeIFN-ω.
Revue Méd. Vét., 2015, 166, 1-2, 25-29
Physical examination revealed white, smooth, flat shiny
plaques and firm, hyperkeratotic, pedunculated cauliflowerlike masses on lips, oral cavity, face and front legs (Fig 1).
Figure 1: Numerous white, smooth, flat shiny plaques and firm, hyperkeratotic, pedunculated cauliflower-like masses were observed on face
and lips.
26
PIN (D.) AND COLLABORATORS
Cytological examination of impression smears revealed
cocci and some degenerate neutrophils. Biopsies were
performed under local anesthesia. Tissue samples were
fixed in 10% buffered formalin and processed routinely.
Histological examination of haematoxylin and eosin stained
sections revealed hyperkeratosis, papillary epidermal
hyperplasia with marked expansion of the stratum corneum.
Keratinocytes of the stratum granulosum contained giant
keratohyalin granules and increased amount of wispy greyblue cytoplasm, consistent with viral cytopathic change
(Fig2). Some koilocytes (keratinocytes with swollen, clear
cytoplasm and a pyknotic nucleus) were observed (Fig2). A
refractory florid papillomatosis was diagnosed.
Figure 3: Histopathological section of cutaneous biopsies (H&E stain,
X40-10), showing hyperkeratosis, relatively uniform papillary epidermal hyperplasia with marked expansion of the stratum corneum.
Keratinocytes of the stratum granulosum contained giant keratohyalin granules and increased amount of wispy grey-blue cytoplasm,
consistent with viral cytopathic change. Some koilocytes (keratinocytes
with swollen, clear cytoplasm and a pyknotic nucleus) were observed.
Figure 2: Same dog as in Fig 1 at week 2. A significant reduction in extension and number of papillomas was observed.
Treatment was initiated with 1 MU/kg rFeIFN-ω given
by subcutaneous injection once daily for 5 consecutive days.
One further 5-day treatment was realized 14 days later.
A shampoo containing 3% of chlorhexidine digluconate
and 0.5% of climbazole (DouxoPyo; Sogeval) was realized
twice a week and followed by application of a moisturizer
(Humiderm; Virbac).
The dog was examined after 2, 4, 8, 12 weeks. After 2
weeks, a significant reduction in extension and number of
papillomas was observed (Fig 3). Only ten small warts were
still present by day 30 on the face. Complete regression of
papillomas in the oral cavity and on the body was observed
by day 50 (Fig 4). There was no recurrence of papillomatosis
in the treated dog during a follow-up period of 12 months.
No adverse effects were seen.
Discussion
Figure 4: Complete regression of papillomas was observed by day 50.
Canine PVs have been associated with exophytic warts
as in canine oral papillomatosis, endophytic warts, and
pigmented plaques and, in some cases, squamous cell
carcinomas [17].
Canine oral papillomas induced by CPV-1 [2] are
common in puppies and are characterized by multiple,
invasive, cauliflower-like hyperkeratotic masses typically
in the oral mucosa including the lips and mucocutaneous
Revue Méd. Vét., 2015, 166, 1-2, 25-29
TREATMENT OF FLORID PAPILLOMATOSIS IN A DOG
junctions. Occasionally, tongue, pharynx and esophagus can
be affected [33]. CPV-1 may also be involved in nonregressing
lesions and the development of squamous cell carcinomas,
endophytic papillomas and cutaneous lesions in haired skin.
[17, 30, 24, 28]. Cutaneous exophytic papillomas may also be
induced by CPV-2, CPV-6 and CPV-7 [17, 34, 18].
In our case, the identification of the papillomavirus has
not been performed.
Papillomatosis in dogs may be a self-limiting disease,
and spontaneous regression of PV-induced exophytic
warts is classically observed 4 to 8 weeks after the onset of
symptoms [17]. Oral papillomas usually regress after 4 to 8
weeks, although they may persist for up to 24 months [32,
22]. Cutaneous papillomas may persist for 6 to 12 months
before undergoing spontaneous regression [32, 22]. The
exact 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 [32, 22]. In one study, Nichols
et al [25], in order to investigate events during regression
of mucosal papillomas, obtained chronologically biopsies
from beagles experimentally infected with canine oral
papillomavirus. Small raised, focal, smooth, domed
single or multiple masses (8-12 mm) appeared 5 weeks
post‑infection; an increasing in size (14mm) of warts with
multiple projecting papillae was observed by week 8 and a
complete disappearance by week 11. Biopsies taken at week
8 showed multiple apoptotic keratinocytes and a prominent
lymphocytic infiltrate that obscured the dermo-epidermal
interface explaining the regression of warts. In our case,
histopathological examination showed neither apoptotic
keratinocytes nor prominent lymphocytic infiltrate, features
compatible with a non-regressing form of papilloma.
Unusually severe or persistent and non self-limiting forms
of papilloma are either associated with immunosuppression,
old age and recent chemotherapy or corticosteroid and
cyclosporine A therapy or without any identifiable underlying
cause [28, 1, 20, 23, 10, 5, 8].
Occasionally, incomplete regression occurs, and a few
papillomas persist indefinitely [32]. Nichols et al described
a case of naturally occurring extensive COPV infection in
which the papillomas failed to regress and were refractory to
all treatments, including vaccination [24].
Breed predispositions putatively associated with an
inherited immune defect may exist, although the available
data are very limited [17, 9]. Sundberg et al reported two Shar
Pei dogs from the same littermate with oral papillomatosis
[28]. In our case informations about others dogs from the
same littermate were not available. In Pug dogs genetic
factors rather than viruses are thought to be primarily
responsible for pigmented papillomas [33].
Revue Méd. Vét., 2015, 166, 1-2, 25-29
27
In our case, spontaneous wart regression was not
observed. Furthermore, classic therapies as magnesium
chloride, spiramycin and metronidazole, and azythromicin
did not result in any improvement. On the contrary, a
deterioration of the condition has been observed.
In human, IFN-α2a has, for several decades, been the
drug of choice to treat recurrent and recalcitrant to therapy
respiratory papillomatosis [16, 29, 15]. In veterinary medicine,
orally human recombinant IFN-α2a has been anecdotally
reported as an adjunct therapy for canine pigmented
plaques in three adult dogs with hyperadrenocorticism and
hypoglobulinemia, hypoglobulinemia, and hypothyroidism
respectively [27]. rFeIFN-ω has been used in dogs as a well
tolerated treatment with no adverse reaction. In laboratory
and field trials the use of rFeIFN-ω has shown to reduce
the mortality rate, clinical signs and lesions associated with
canine parvovirus [7] but it has not been tested in canine
papillomatosis.
The interferons are a group of cytokines produced
by leucocytes in response to viral, bacterial and tumoral
stimulation [26] but the exact mechanisms of action have not
been fully elucidated.
One possibility is enhancement of an immunological
response against the PV-infected cells, for example by
increasing major histocompatibility complex (MHC)
expression [26]. An increase in MHC expression would
consequently increase the ability of the immune system to
respond to and combat PV infection [12].
Another possibility could be that IFN increases the rate
of apoptosis in virus-infected cells [29]. IFN-α is also known
to exert anti-proliferative effects in many cell types and this
has been suggested to be of importance in its anti-neoplastic
activities [26].
In our case, surgical removal or topical application
of drugs was not possible and other classical therapies as
magnesium chloride, spiramycin and metronidazole and
azithromycin have not been effective.
On the contrary, the lesions significantly improved 1 week
after the first course of 5-day treatment and disappeared
following the second 5-day treatment with 1 MU/kg
rFeIFN-ω given subcutaneously.
Even though further studies in double-blind, placebocontrol, are necessary to confirm the therapeutic efficacy
of rFeIFN-ω in canine papillomatosis, we think that a
delayed spontaneous regression is unlikely due to the
histopathological findings, the rapid response to treatment
and the significant reduction in extension and number of
papillomas at 2 weeks.
28
Acknowledgements
The authors would like to express their thanks to Virbac
which provided a part of the drugs for the study.
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