Signalment:  

17-year-old male neutered domestic shorthaired cat, (Felis cats).The cat presented with a 1-year history of severe conjunctivitis and corneal ulceration with secondary corneal sequestrum formation. Clinically, a collapsed anterior chamber, symblepharon, blepharospasm and protrusion of the third eyelid were observed. Additionally, the cat had chronic corneal disease that was considered a sequel to poorly managed feline herpes virus-related keratoconjunctivitis when it was young. Due to a poor prognosis, the eye was enucleated and sent to the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) at the University of Wisconsin-Madison.

Gross Description:  

There is diffuse white to tan opacification and thickening of the peripheral cornea and limbus extending concentrically towards the axial cornea. The most axial cornea surface is depressed and ulcerated, presenting moderate brown discoloration at the periphery and center of the ulceration. On cut section the corneal profile, limbus, equatorial sclera, episclera, and ciliary body stroma are expanded by a white, firm and irregular tissue. The anterior surface of the iris is thickened and irregular. The posterior aspect of the globe is grossly normal.

Histopathologic Description:

There is a poorly delineated, highly infiltrative and highly cellular neoplastic tissue infiltrating, expanding and partially replacing the superior and inferior limbus, extending approximately 8 mm into the peripheral cornea, affecting the superficial 2/3 of the stroma. The neoplastic tissue also infiltrates the conjunctival substantia propria, equatorial sclera and episclera, ciliary body stroma, base of the iris and trabecular meshwork causing complete collapse of the iridocorneal angle. A second, distinctive pattern of infiltration is present with the neoplastic cells carpeting the anterior and posterior iris surfaces, the surface of the ciliary body plicae, trabecular meshwork beams, and the ulcerated corneal surface, mimicking the corneal epithelium. Neoplastic cells are arranged in cords and nests, sometimes forming anastomosing trabeculae, and are supported by abundant fibrovascular stroma (desmoplastic reaction). Multifocally there is keratinization and sloughing of the neoplastic cells in the center of neoplastic nests. Neoplastic cells present moderate amounts of eosinophilic cytoplasm with variably distinct cell borders, oval nuclei with coarsely stippled chromatin and usually one large central magenta nucleolus. There are 32 mitotic figures in 10 hpf. Cellular pleomorphism is marked with multiple karyomegalic cells and atypical mitotic figures. Neoplastic cells are also seen infiltrating and completely filling and expanding multiple vascular profiles in the equatorial sclera, ciliary body and iris stroma, and peripheral and peri-papillary choroid. There is diffuse corneal ulceration and marked loss of axial corneal stroma (facet lesion). The peripheral corneal stroma presents focally extensive areas of liquefaction of the corneal lamellae (collagenolysis) with accumulation of fine nuclear debris. There is moderate vascularization of the deep corneal stroma and moderate infiltration of neutrophils. There are diminished numbers of ganglion cells in the inner retina.

Morphologic Diagnosis:  

1. Eye, Metastatic carcinoma.
2. Cornea, severe and diffuse ulcerative and collagenolytic keratitis with axial facet lesion formation.
3. Retina, Marked and diffuse ganglion cell layer atrophy.

Lab Results:  

Mildly increased intraocular pressure (25mmHg) and positive fluorescein stain in the central cornea.

Condition:  

Globe with metastatic carcinoma

Contributor Comment:  

Metastases to the eye are less frequently diagnosed than primary ocular tumors.(1,2,3,4) Despite this, the rich vascularization of the uveal tissue and the immune privilege associated with the intraocular environment favor the globe as a site for metastatic disease.(2) Ocular metastases have been diagnosed in cats with many forms of malignant neoplasia. Pulmonary carcinoma, squamous cell carcinoma of undetermined origin, mammary adenocarcinoma and fibrosarcoma are the most commonly reported.(1,3) There are 4,542 cases of feline ocular neoplasia in the COPLOW collection database. Of those, 580 are metastatic tumors (12%), 423 of which are lymphoma (72%). The remaining 157 metastatic, non-lymphoma cases are described in Table 1.

Table 1. Cases of feline metastatic tumor to the eye on the COPLOW database

			Cases	%
Feline ocular tumors (total)			4,542
Feline metastatic tumors to the eye			580	12% of total cases
1. Lymphomas			423	72% of metastatic cases
1. Non-lymphoma			157	28% of metastatic cases
	a. Undifferentiated neoplasia		05	3.1% of non-lymphomas
	a. Sarcoma		25	15.9% of non-lymphomas
	a. Carcinoma		127	81% of non-lymphomas
		- Undifferentiated carcinoma	74	58.2% of carcinomas
		- Pulmonary carcinoma	24	18.8% of carcinomas
		- Squamous cell carcinoma	24	18.8% of carcinomas
		- Mammary carcinoma	03	2.3% of carcinomas
		- Anal sac adenocarcinoma	01	0.7% of carcinomas
		- Uterine carcinoma	01	0.7% of carcinomas

Common morphologic features of metastatic neoplasia in cat eyes include(1):

1. Uni- or bilateral uveal metastases.
2. A tendency to affect the choroid more often than the anterior uvea.
3. When the anterior uvea is affected, neoplastic cells line or carpet the surfaces of the iris and ciliary body.
4. Extensive and widespread invasion of blood vessels. 
5. A pattern of choroidal infarction with characteristic, wedge-shaped areas of tapetal discoloration and profound vascular attenuation visible on funduscopy.
6. Orbital involvement may accompany involvement of the posterior segment of the globe. 

The present case shows most of the previously described common morphologic features of metastatic neoplasia. Of those features, the lining of ocular surfaces and the marked vascular invasion especially of the choroidal vessels are the most salient. Interestingly, the neoplastic cells also produce an unusual pattern of carpeting by proliferating over the ulcerated corneal surface, mimicking the corneal epithelium. The absence of the native corneal epithelium and subsequent exposure of the corneal stroma might have facilitated/stimulated neoplastic cells to proliferate in that pattern. 

The neoplastic tissue presents classic epithelial morphology with multiple areas developing keratinization of the inner cellular layers. This feature points towards a squamous cell carcinoma, but other undifferentiated carcinomas with squamous metaplasia cannot be ruled out.

Other possible differential diagnoses include pulmonary carcinomas, primary corneo-conjunctival squamous cell carcinomas and mammary carcinomas. Metastatic pulmonary carcinomas tend to form acinar/glandular structures on the uveal tissue and/or present ciliated epithelium carpeting the ocular surfaces. Primary ocular squamous cell carcinomas in cats can invade the intraocular structures, especially the anterior chamber and uvea, but they seldom infiltrate vessels and the posterior aspect of the globe.(4) Metastatic mammary carcinoma is a remote possibility since the cat in this case is male and neutered.

The decrease number of ganglion cells in the retina confirms the clinical diagnosis of secondary glaucoma. In cats, the main histologic feature of glaucoma is loss of ganglion cells without progressive degeneration of the outer retina, as seen in dogs.(1) The majority of glaucomas in cats are secondary to other ocular diseases, most notably chronic lymphoplasmacytic anterior uveitis, systemic hypertension-related intraocular hemorrhages, and intraocular neoplasia.(1,2)

The patient in the present case was lost to follow-up before the identification of a primary tumor.

JPC Diagnosis:  

Eye, globe: Carcinoma, poorly differentiated with drainage angle occlusion, retinal atrophy, multifocal detachment, ulcerative keratitis with axial facet lesion formation and numerous tumor emboli.

Conference Comment:  

We thank the contributor for providing this unique, interesting case as well as a comprehensive review of primary and metastatic ocular tumors in cats. The notes on salient histopathology findings in primary versus metastatic ocular tumors are especially relevant. Prior to the conference, the moderator led a particularly informative discussion encompassing normal ocular anatomy and physiology, touching upon the concept (also noted by the contributor) that the abundant uveal vascularization and associated immune privilege of ocular tissue provide a favorable environment for tumor metastasis; however, the moderator pointed out that these conditions are also advantageous for the development of primary ocular tumors. So, while this neoplasm admittedly exhibits similar morphologic features to those described above for metastatic ocular tumors, the moderator suggests that definitive differentiation from a primary tumor is quite difficult, and likely requires identification of the initial tumor at another anatomic location. 

Many conference participants tentatively identified this tumor as squamous cell carcinoma (SCC). Ocular involvement of SCC is most common in cattle and horses, but has also been reported in cats and dogs. In all domestic species, SCC involving the ocular surface appears to have a preference for the limbus (corneoscleral junction) which is the transition zone between the corneal and conjunctival epithelial cell populations. The limbus is home to the local stem cell population; stem cells have a high proliferative capacity, are susceptible to the accumulation of oncogenic mutations, and are thought to be the source of many neoplasms. Corneolimbal SCC refers specifically to a neoplasm originating at the limbus with extension into the cornea (as opposed to originating from the corneal epithelium itself).(4) This neoplasm manifests several histologic features suggestive of corneolimbal SCC: neoplastic cells are most numerous in the sclera, ciliary body and limbus, there is fairly prominent intracellular bridging with moderate desmoplasia and there is scattered infiltration of neutrophils; however, participants did not appreciate significant dyskeratosis or formation of keratin pearls, so we are unable to definitively diagnose ocular SCC. The contributor provides a brief, but thorough differential diagnosis for the gross and microscopic lesions in this case.

References:

1. Dubielzig RR, Ketring KL, McLellan GJ, et al. Veterinary Ocular Pathology: a Comparative Review. London: Elsevier; 2010.

2. Grahn BH, Peiffer RL. Fundamentals of veterinary ophthalmic pathology. In: Gelatt KN, ed. Veterinary Ophthalmology. 4th ed. Victoria: Blackwell Publishing, 2007:411-502.

3. Wilcock BP. The eye and ear. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 1. 5th ed. Philadelphia: Elsevier; 2007:459552.

4. Scurell EJ, Lewin G, Solomons M, et al. Corneolimbal squamous cell carcinoma with intraocular invasion in two cats. Vet Ophthalmol. 2013 Feb 20. doi: 10.1111/vop.12036. [Epub ahead of print]

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