Report of a self-resolving corneal viral papilloma in a dog

Abstract

A 10-month-old male castrated beagle dog, without prior history of ocular disease, was referred for a corneal mass of the right eye. A non-painful raised mass with frond-like projections originated from the dorsotemporal paraxial cornea of the right eye. In addition, a plaque-like conjunctival lesion and several raised, smooth masses of the eyelid were noted around the right eye. An incisional biopsy of the corneal mass and an excisional biopsy of the conjunctival mass were performed. Histopathology confirmed the clinical diagnosis of viral papilloma. Conservative management with monitoring was elected, and the lesion self-resolved 3 mo after initial appearance.

Key clinical message:

This case suggests that monitoring is appropriate for corneal lesions definitively diagnosed as viral papillomas, as they may be self-limiting.

Papillomas are benign proliferations of epithelial origin and most commonly affect mucosal surfaces and skin. When ocular tissues are affected, the eyelid skin or the mucocutaneous junction of the eyelid margin is often the site of origin, and the conjunctiva and cornea are rarely involved (1). Periocular papillomas are divided into viral, squamous, and reactive papillomas based on their histologic characteristics (2). Viral papillomas are the result of infection with canine papillomavirus and often spontaneously regress (3).

All previous reports in the veterinary literature of papillomas of the cornea have been in animals with a history of chronic corneal disease, most commonly keratoconjunctivitis sicca, and only 1 case report has had evidence of papillomavirus infection (4–7). These animals were treated with keratectomy, chemotherapeutics, or strontium-90 brachytherapy with subsequent improvement or resolution of their lesions. The present case describes a dog with a confirmed corneal viral papilloma that self-resolved with conservative medical management.

Case description

A 10-month-old, 14.2 kg, castrated male beagle dog was presented to the Oklahoma State University Boren Veterinary Medical Hospital with a 4- to 5-week history of a mass on the right cornea. The mass was slowly increasing in size and the dog was non-painful until 2 d prior to presentation, when the owner noted the dog rubbing its right eye. Previously, a mass had been removed from the skin near the lateral canthus of the right eye, but the mass was not submitted for histopathological assessment. The dog otherwise had no prior history of ocular disease and was considered systemically healthy.

On examination, the right eye appeared comfortable. A white-yellow mass protruded from the dorsotemporal cornea, covering approximately 15 to 20% of the corneal surface, without limbal involvement. The mass had numerous frond-like projections from its anterior surface. There was active keratitis surrounding the mass, as indicated by the presence of corneal vascularization and edema. Additional masses were noted on the periocular tissues of the right eye. These included a pink, plaque-like lesion on the palpebral conjunctiva of the upper eyelid and several smooth, round, pink to brown masses on the skin of the upper and lower eyelids (Figure 1). Schirmer tear testing confirmed that tear production was normal in the right eye (28 mm/min) and mildly reduced in the left eye (13 mm/min). Intraocular pressure was 5 mmHg in the right eye and 20 mmHg in the left eye, suggestive of anterior uveitis in the right eye, although no other changes consistent with uveitis were noted on examination. Fluorescein staining did not detect corneal ulcers in either eye. The remainder of the ophthalmic examination was unremarkable.

Figure 1.

Right eye upon initial presentation. A raised, white-yellow mass was noted at the dorsotemporal cornea, with several frond-like structures on its surface. This mass was not associated with the limbus and was surrounded by a ring of edematous corneal stroma. Several raised, pink to brown smooth dermal masses were noted on the upper and lower eyelids. In addition, a conjunctival plaque was present on the dorsal palpebral conjunctiva (not shown).

Following the topical application of 0.5% proparacaine hydrochloride, an incisional biopsy of the corneal mass was conducted, and the conjunctival plaque was completely excised. The tissues were placed in 10% buffered formalin and submitted for histopathology. The dog was prescribed neomycin-polymixin-bacitracin ophthalmic ointment 3 times daily for 1 wk in the right eye.

The tissue samples were processed routinely, sectioned, stained with hematoxylin and eosin, and examined with light microscopy. The conjunctival sample had extensive epithelial proliferation with development of epidermis-like layers. This included a prominent stratum granulosum with keratohyaline granules, and stratum corneum with mild orthokeratotic hyperkeratosis. Occasional koilocytes were noted in the stratum spinosum and granulosum (viral cytopathic effect). The superficial corneal sample was composed mostly of thickened stratum corneum with marked hyperkeratosis. Some keratinocytes in the corneal sample had keratohyaline granules and intranuclear viral inclusion bodies (Figures 2, 3). The findings of both samples were consistent with viral papillomas.

Figure 2.

Superficial biopsy of canine corneal viral papilloma. The sample consists entirely of large hypereosinophilic keratinized keratinocytes with multifocal intercellular accumulations of homogenous eosinophilic proteinaceous material (fluid). Hematoxylin and eosin (H&E), scale bar = 200 μm.

Figure 3.

Superficial biopsy of canine corneal viral papilloma. Characteristic features of viral papillomas in this sample include prominent basophilic keratohyaline granules (arrow) within keratinized keratinocytes and eosinophilic intranuclear viral inclusion bodies (black circle). H&E, scale bar = 20 μm.

Upon recheck 20 d later, the corneal mass was slightly smaller and smoother in appearance and the remaining periocular masses had undergone significant regression. The cornea remained fluorescein negative. Schirmer tear testing and intraocular pressures were not performed at this visit. Dense, mid-stromal corneal vascularization had progressed around the mass extending across the temporal 2/3 of the cornea, leading to reduced vision in the eye. A menace response was still present and the intraocular structures that could be evaluated were unremarkable. Ongoing monitoring was elected as the lesion was decreasing in size and the associated keratitis was not painful. Although no blepharospasm was noted, the owner elected to treat with a lubricating gel (Optixcare Eye Lube; Aventix, Burlington, Ontario, Canada) twice daily to prevent irritation.

Recheck was performed 52 d after presentation, and both the corneal and periocular masses had resolved, with only faint corneal fibrosis noted over the initial site of the mass (Figure 4). Although corneal vascularization remained, all vessels were significantly attenuated and only seen in the dorsotemporal quadrant. The cornea remained fluorescein negative. Schirmer tear testing was not performed at this visit and intraocular pressures were normal in both eyes (14 and 13 mmHg in the right and left eyes, respectively). Given that the eye was comfortable and visual at that time, no further treatment or follow-up was recommended.

Figure 4.

Final appearance of the cornea following regression of the papilloma, 52 d after biopsy, leaving an area of faint fibrosis.

Discussion

Most papillomas are thought to be of viral origin, induced by a papillomavirus that is usually species-specific and has a tropism for mucosal and cutaneous epithelium (3). Viral-induced papillomas are generally considered a transient disease of younger animals, with the mean age of 3.1 y in dogs with the cutaneous form (3) and 3.7 y in dogs with conjunctival involvement (8). Papillomas present grossly as masses with a raised, plaque-like appearance with multiple fronds, with or without pigmentation (8). Histologically, viral-induced papillomas display prominent hyperkeratosis and demonstrate viral cytopathic effects, including koilocyte formation; they may have intranuclear inclusion bodies (3,8). In dogs, some papillomas affecting conjunctival tissue contained DNA from canine oral papillomavirus (COPV), a pathogen known to cause lesions of the oral cavity, lips, and skin (9). Based on dogs experimentally inoculated with COPV into their mucosal tissues, tumors typically take 4 to 8 wk to develop and then experience an inflammatory period, consisting primarily of a migration of T-lymphocytes, followed by rapid regression of the lesions (10).

A second type of papilloma, squamous papilloma, has recently been described affecting ocular tissues (8). Squamous papillomas are not associated with viral infection and currently have an unknown etiology (8). These tumors are usually pigmented and associated with a large feeder vessel; they are typically smaller than virally induced papillomas (8). Histologically, these tumors do not have evidence of hyperkeratosis or koilocytes, but consist of delicate, sharply pointed fronds extending from a fine core of fibrovascular tissue (8). In the veterinary literature, these tumors have been exclusively described as conjunctival lesions from dogs and tend to occur in an older population of animals (mean age: 9.4 y) (8).

Although not reported in the literature, another classification anecdotally reported is the reactive papilloma. Reactive papillomas are associated with inflammation or neoplasia and are composed of proliferative epithelium forming rounded papillary projections (2). Both squamous and reactive papillomas lack the marked hyperkeratosis, viral cytopathic effects, and viral inclusion bodies associated with papillomavirus infection (2). Neither squamous papillomas nor reactive papillomas are expected to regress spontaneously. Mechanical irritation and actinic radiation have been postulated to be contributing factors toward the development of ocular papillomas in both humans and animals (4,5,11). Solar elastosis, one of the histopathological changes that occurs with chronic actinic radiation exposure, is characterized by basophilic elastic fiber accumulation in the dermis or conjunctival substantia propria. In humans, conjunctival papillomas that were negative for human papillomavirus (HPV) had a significantly greater frequency of elastosis relative to conjunctival papillomas that were positive for HPV (11).

In the present case, an intense vascular response was noted upon recheck examination 3 wk after initial presentation. Based on the report by Nicholls et al (10) describing experimental inoculation of COPV, perhaps the vascular response was associated with a T-lymphocyte-driven inflammatory response that has been seen with regression of viral papilloma, but this was not confirmed histologically. There was minimal inflammation at first presentation, and the vascular response markedly worsened after examination and biopsy. In the human literature, a case of dermal warts caused by HPV was reported to undergo spontaneous regression following biopsy, despite having shown no evidence of improvement over the prior 6 mo. This was proposed to be due to an increase in host immune response following exposure to viral antigens secondary to the trauma from the biopsy (12). Perhaps biopsy of the corneal or conjunctival mass triggered a similar immune response and expedited regression. Alternatively, the keratitis noted at the first examination may have represented the beginning of an immune response, which would have progressed to resolution of the lesion regardless of biopsy.

Hypotony was noted in the affected eye at initial presentation, which suggests anterior uveitis was present. Axonal reflex uveitis secondary to corneal trauma is described in both human and veterinary literature. It is thought that stimulation of the trigeminal nerve causes an antidromic impulse that activates the parasympathetic fibers of the third cranial nerve and subsequently causes breakdown of the blood-aqueous barrier (13–16). We suspect that the papilloma-induced keratitis led to secondary reflex uveitis in this case. More significant signs of uveitis, such as blepharospasm, aqueous flare, and miosis, were not seen at any time. Since the uveitis was not accompanied by other clinical signs, treatment was not initiated. Despite lack of treatment, uveitis was considered resolved at final examination of the patient as intraocular pressures had normalized.

Cases of corneal papilloma are rare in human and veterinary literature (4,17). Reports in veterinary species include dogs, as well as a camel and a tapir, and all animals were at least 2 y of age and had a prior history of chronic corneal disease (4–7). Bonney et al (18) described a case of a young dog developing a papilloma involving the cornea with no prior history of ocular disease. This mass was located at the limbus and was thought to arise from conjunctival tissue; the papilloma was treated with complete surgical excision. In all published cases of corneal papilloma, clinicians elected removal of the mass via superficial or mid-stromal keratectomy (4–7,18). Our case is unique in that the dog presented with a corneal mass consistent with a viral papilloma, without a history of prior ocular disease or evidence of past corneal disease on examination, that self-resolved without surgical removal.

Keratectomy is an invasive surgical procedure requiring anesthesia and specialized training and equipment; it may present considerable expense to an owner. In addition, surgical excision may not offer a definitive cure, as recurrence of conjunctival papillomas has been reported in both dogs and humans, sometimes after multiple excisions (9,19). In the present case, definitive diagnosis was obtained with an incisional biopsy performed with sedation and topical anesthesia. The papilloma resolved spontaneously 3 mo after initial presentation. This resulted in a good clinical outcome for the patient without the need for an invasive surgical procedure and general anesthesia. It is therefore reasonable to suggest that delaying surgical removal of viral papillomas may be appropriate in cases in which the lesion does not obstruct normal function of the eyelids or cause signs of discomfort to the animal. However, it is noteworthy that in both human and veterinary literature, there are several reports of malignant transformation of papillomas to squamous cell carcinoma, including tumors of the conjunctiva, particularly when papillomavirus is a causative agent (19–21). In immunocompetent animals, such transformation is thought to be linked to UV light exposure, with the papillomavirus preventing apoptosis of UV-damaged cells (22). Whether such a transformation could occur in the case of a corneal papilloma is unknown; however, when monitoring for regression is selected instead of more aggressive surgical management, close follow-up is strongly recommended. Should progression be noted, or if the tumor is not resolving in an expedient manner, aggressive management with keratectomy, with or without ancillary therapy such as cryotherapy or topical chemotherapy, should be considered. CVJ