Diagnostic Ophthalmology

History and clinical signs

A 10-year-old castrated male Devon Rex cat was referred to the ophthalmology service at the Western College of Veterinary Medicine (WCVM) for evaluation of bilateral conjunctivitis present for the preceding 8 mo. Prior to referral, the conjunctivitis had, on separate occasions, been treated with oral prednisolone (10 mg, PO, q12h), subcutaneous cefovecin injection (Zoetis, Kirkland, Quebec), and topical neomycin/polymyxin B/bacitracin (Vétoquinol, Lavaltrie, Quebec). The client and referring veterinarian noted a marked improvement on the oral steroids, and a rapid relapse when they were discontinued. Upon admission, the menace responses, palpebral, oculocephalic, and direct and consensual pupillary light reflexes were present bilaterally. Schirmer tear test (Schirmer Tear Test Strips; Alcon Canada, Mississauga, Ontario) values were 19 and 22 mm/min in the right and left eyes, respectively. The intraocular pressures were estimated with a rebound tonometer (Tonovet; Tiolat, Helinski, Finland) and were 21 mmHg bilaterally. Fluorescein staining (Fluorets; Bausch & Lomb Canada, Markham, Ontario) was negative bilaterally. On direct examination, the conjunctivae were hyperemic with mild chemosis in the left eye and marked chemosis in the right eye. The third eyelid in the right eye appeared to have a small notch defect. Corneal vascularization was present bilaterally, albeit more significantly in the right eye. In addition, there was central corneal fibrosis in the right eye. Following application of 0.5% tropicamide (Mydriacyl; Alcon Canada, Mississauga, Ontario), biomicroscopic examination (Kowa SL-17; Kowa, Tokyo, Japan) revealed no further abnormalities. Indirect ophthalmoscopic (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) examinations were completed bilaterally and no further abnormalities were detected. Photographs of both eyes are provided for your assessment (Figure 1).

Figure 1.

The right (A) and left (B) eyes of a 10-year-old Devon Rex cat presented for persistent bilateral conjunctivitis. Conjunctival hyperemia and chemosis are worse in the right eye (A).

What are your differential diagnoses, therapeutic plan, and prognosis?

The most common differentials for feline conjunctivitis are the infectious agents feline herpesvirus type 1 (FHV-1), Chlamydophila felis (C. felis), and Mycoplasma spp. (1–4). Uncommon infectious differentials for feline conjunctivitis include calicivirus and parasites (5–8). Non-infectious causes for feline conjunctivitis include feline eosinophilic conjunctivitis (FEC), lipogranulomatous conjunctivitis, tear film or eyelid abnormalities, and neoplasia (9–11).

Infectious agents are the most frequent cause of feline conjunctivitis and should be the first consideration. Attempting to differentiate these through laboratory testing is often unrewarding. Cytology from conjunctival scrapings is often recommended to evaluate for epithelial cell inclusion bodies present within the cytoplasm in early infection with C. felis and Mycoplasma spp., and within the nuclei of FHV-1; however, these are rarely detected in practice (12–14). Virus isolation and fluorescent antibody (FA) testing for FHV-1, and culture for C. felis and Mycoplasma spp. require specialized transport media and laboratory techniques and have variable sensitivity (4). Polymerase chain reaction (PCR) testing is available for FHV-1, C. felis, and Mycoplasma spp. However, false positives and false negatives occur, and the reliability of PCR in confirming a definitive etiology in a clinical setting is questionable (15). Because of difficulties in establishing a definitive etiological cause for conjunctivitis using these diagnostic tests, presumption of an infectious cause is often speculated based on a combination of history, clinical signs, clinical course, and response to previous therapy.

Ocular examination findings are often suggestive of noninfectious causes of conjunctivitis such as FEC, lipogranulomatous conjunctivitis, tear film and eyelid abnormalities, and neoplasia. Cytology is useful for diagnosis of FEC as finding even one eosinophil in a conjunctival or corneal scraping is said to be diagnostic for FEC (9). Histopathology from conjunctival biopsy of representative lesions is an excellent means to confirm a diagnosis of FEC, lipogranulomatous conjunctivitis, and neoplasia (9,10). A biopsy is recommended whenever thickened or proliferative tissue is present. Due to the thickened nature of the conjunctiva in the right eye, and a history that did not support infectious cases of conjunctivitis, a conjunctival biopsy was completed in this case.

Histopathology revealed a marked, lichenoid, lymphocytic-plasmocytic conjunctivitis with edema (Figure 2). Although a definitive diagnosis was not revealed, given the historical positive response to steroids, an infectious cause was thought less likely, and a further course of corticosteroid treatment was instituted. Topical prednisolone acetate 1% (Sandoz Prednisolone; Sandoz Canada, Boucherville, Quebec), q8h in the right eye and q12h in the left eye, and oral prednisolone (Rafter 8 Products, Calgary, Alberta), 7.5 mg, PO at a tapering dose, was initiated. A recheck examination was recommended in 3 wk but declined by the owner due to financial constraints.

Figure 2.

Initial conjunctival biopsies revealed a marked infiltrate of lymphocytes, plasma cells, and occasional neutrophils within the lamina propria and epithelium.

The cat returned 11 mo later for re-evaluation. The owner reported an initial positive response to the corticosteroid therapy but recent reoccurrence with worsened and persistent clinical signs. At this examination, the conjunctiva in the right eye was markedly hyperemic and chemotic, the gland of the third eyelid had prolapsed, and a multi-lobular flocculant mass was protruding from its posterior surface (Figure 3). The cornea was edematous with peripheral vascularization and superficial pinpoint ulcerations. Examination of the left eye was within normal limits. The presence of unilateral conjunctivitis with punctate corneal ulceration was feasibly consistent with FHV-1 keratoconjunctivitis (2,3). Therefore, trial therapy was initiated including topical antiviral therapy with compounded 0.1% Idoxuridine (Summit Veterinary Pharmacy, Aurora, Ontario) and topical 0.3% Ofloxacin (Allergan, Unionville, Ontario), each administered q6h in the right eye. The cystic appearance of the third eyelid was considered highly abnormal and en-bloc resection of the third eyelid was recommended for histopathology. This was conducted 1 mo later.

Figure 3.

Photograph of the right eye of a 10-year-old Devon Rex cat after a mass had grown on the third eyelid.

Light microscopic examination of the third eyelid revealed multiple islands and nests of squamous epithelial cells within the substantia propria with varying cellular and nuclear size, and a moderate number of mitotic figures consistent with a diagnosis of squamous cell carcinoma (SCC) of the third eyelid (Figure 4). There was an extensive mixed inflammatory conjunctivitis surrounding the neoplasm and throughout the conjunctiva. The margins of the biopsy appeared to be free of neoplastic cells.

Figure 4.

Light microscopy of the third eyelid revealed multifocal areas of neoplastic squamous cells surrounded by a dense lymphocytic plasmocytic inflammatory infiltrate. 5×, black bar = 50 μm.

Squamous cell carcinoma is the most common neoplasm of the eyelids and nictitating membrane (11). It can also affect other ocular structures including the conjunctiva, cornea, and orbit (16–18). Cases of intraocular invasion from extraocular masses have been reported (17,19). Squamous cell carcinoma of the third eyelid can present as an obvious mass or roughened area (20), multifocal, exophytic papilloma-like lesions, or aggressive infiltrating carcinomas with penetration of the globe or destruction of orbital tissue (17,21). However, cats may present with only epiphora and an “irritated” surface in mild cases (20). Chronic inflammation of the conjunctiva occurs in conjunction with SCC in cats (21).

Several major risk factors are involved in the pathogenesis of cutaneous SCC, including coat color, age, and prolonged exposure to sunlight. Prevalence of cutaneous SCC increases in white or light-colored cats, likely due to a lack of protective pigmentation (22). Squamous cell carcinoma is more common in middle-aged to older cats (22,23), often affecting areas of increased exposure to sunlight (22). Ultraviolet radiation causes mutations in the tumor suppressor gene p53, a gene that codes for a protein involved in the cell cycle and tumor suppression (24). There is an abnormal accumulation of this protein in conjunctival SCC of domestic animals, including cats (24,25).

Ocular SCC can be locally aggressive, invading adjacent ocular structures and the orbit (26), and has a postoperative recurrence rate as high as 70% (27). It usually metastasizes late via lymphatics (28). A definitive diagnosis of SCC can be obtained by biopsy (20). Once diagnosed, a thorough assessment of the orbit, regional lymph nodes, and distant sites for metastases or tumor extension should be completed. Metastatic SCC must also be considered as tumors of the lung and middle ear can spread to the conjunctiva and uvea (19). Excision of third eyelid SCC may include the free margin of the nictitating membrane alone, or excision of the entire third eyelid in more advanced disease (20,27). Due to the locally invasive nature and high recurrence rate of SCCs, enucleation or exenteration may be recommended depending on staging (27). The prognosis of ocular SCC is guarded if the tumor extends deep into the orbit (20).

Chronic antigenic stimulation from infectious agents has been implicated in the etiology of some neoplasms, by causing a complex immune cascade that results in clonal B-cell or plasma cell expansion (29). Chronic irritation has been proposed as a predisposing factor for the development of SCC in dogs (25,26), whereas infection with Feline Immunodeficiency Virus (FIV) has been associated with SCC in cats (30). In the current case it is possible that a chronic conjunctivitis of an undiagnosed etiology (such as FHV-1, C. felis, or Mycosplasma spp.) had a role in the development of the SCC due to chronic inflammation. The initial conjunctivitis was bilateral in nature, which may support this theory. Given the frequency of infectious conjunctivitis and SCC in cats, sequential development is also conceivable. It is also possible that the initial biopsy was too superficial to have captured representative tissue and only revealed the surrounding inflammation.

Chronic conjunctivitis in cats can be a frustrating condition to diagnose and treat. Results of diagnostic testing may be non-specific or unrewarding. Response to therapy is helpful to support a presumed diagnosis; however, it is important to repeat testing when response to therapy is not as expected. Following the diagnosis of SCC, additional staging to evaluate for metastasis was recommended for this cat. Also, although the surgical margins appeared to be free of tumor cells, due to the extensive nature of the disease surrounding the right eye, an exenteration was advised but declined. The prognosis for this cat remains guarded due to the high frequency of local invasion and recurrence for SCC.