OCULAR PATHOLOGY

Brian Wilcock, D.V.M., Ph.D.

Ocular pathology remains an unfamiliar field for most veterinary pathologists. The reasons for the reluctance to
embrace ocular pathology probably stem from fear of a complex ocular anatomy with which most pathologists are
not comfortable, an unnecessarily complex and unique vocabulary, and rapidly advancing clinical sophistication
which has created a seemingly endless list of specific ocular syndromes that are often specific for particular ages,
species, and even breeds. In this last respect the evolution of veterinary ophthalmology parallels the evolution of
veterinary dermatology, since in both specialties the clinical specialist also acts as the gross pathologist. We
pathologists are in the role of attempting to provide the histologic basis for the clinically observed gross lesions.
Rather than embark upon an encyclopedic overview of ocular pathology, I thought it would be most useful to give
you the tools you will need to interpret some of the most common ocular lesions that you are likely to receive. In
reality, the current world of veterinary ocular pathology is very much dominated by dogs and cats, with a negligible
participation by food producing species. I am more likely to receive a sample from a lizard than from a sheep, pig,
or cow! That huge bias will be reflected in these notes.
In order of prevalence, the most common samples that you are likely to see will be extraocular tumor nodules and
other proliferative lesions, endstage globes with chronic glaucoma, intraocular neoplasms, or intractable uveitis,
ocular eviscerations from animals with chronic glaucoma, conjunctival biopsies from intractable chronic
conjunctivitis, and superficial keratectomy specimens. I will deal with some of these as a specific entity later. First
we need to embark on an overview of the general pathology of the various ocular tissues, and then a discussion of
some of the specific ocular syndromes with which you must be familiar if your reports are to be clinically relevant.

OCULAR GENERAL PATHOLOGY

Background:
There are no reactions that are unique to the globe, but the familiar general pathology events of degeneration,
necrosis, vascular alterations, inflammation, repair and neoplasia are sometimes altered in their manifestation and/or
their significance by a few factors related to unique ocular anatomy and physiology. Some of the contributors to the
uniqueness of ocular pathology include:

1. An unusually strong structural: functional interdependence, with intolerance for even minor imperfections
• corneal and lenticular clarity are disrupted by minor degrees of edema that, in almost any other tissue,
would be insignificant and even imperceptible
• minor serous effusion from the choroid habitually causes retinal detachment, which leads to instant
blindness and, in just a few days, to significant photoreceptor degeneration
• inflammatory disease within the uveal tract changes of the quantity and quality of aqueous humor
production, leading to cataract
• granulation tissue that is entirely appropriate in the context of wound healing may cause traction retinal
detachment, pupillary block glaucoma, or visually-significant corneal opacity
• even mild corneal disease causes a “bystander” anterior uveitis

2. For most ocular tissues, very limited regenerative capacity and a propensity for scarring
• the adult retina and corneal endothelium have no regenerative capacity
• the corneal stroma and the lens have poor regenerative capacity
• fibrous metaplasia is a very common phenomenon within the globe, and is a frequent response of corneal
endothelium, lens epithelium, and retinal pigmented epithelium

3. The globe is a closed system that promotes sharing of chemical messengers and inhibits removal of these
messengers and other potentially harmful humoral and cellular factors

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• injury to any part of the globe may result in an inflammatory or reparative reaction virtually anywhere else
within the globe
• chemical mediators or growth factors “intended “for use in one part of the globe will often, seemingly by
accident, impact on a distant part of the globe (preiridal fibrovascular membrane secondary to retinal
detachment, corneal stromal vascularization secondary to uveitis, cataract secondary to retinal
degeneration, etc.)

CORNEA
The most frequent reactions of cornea to injury are necrosis, inflammation and cutaneous metaplasia.

Corneal necrosis and healing

The significance, sequels, and resolution of corneal necrosis are determined by the depth of injury and the presence
or absence of sepsis. To bring simplicity to a very complex situation, the significance of corneal epithelial necrosis
is related to the immediate and unavoidable development of osmotic corneal edema, and the opportunity for
opportunistic infection. Following loss of the hydrophobic epithelial barrier, there will be instant osmotic edema
and migration of leukocytes from the corneal tear film into the stroma. In the absence of sepsis, those leukocytes
will not be numerous enough to have any untoward effects related to stromal lysis or generation of angiogenic
growth factors. Shallow, nonseptic wounds will heal rapidly by a process of hemidesmosomal lysis, epithelial
sliding along the surface of the preexistent stromal scaffold, cessation of sliding via contact inhibition, and then
gradual normalization of epithelial structure and stromal adhesion. The epithelial sliding occurs rapidly (up to
several millimeters a day), but the process of normalization may take months. The injured epithelium will produce a
new basement membrane and hemidesmosomes
.
If the original injury has cause substantial loss of stroma, or if the bystander injury from neutrophilic inflammation
has destroyed the superficial stroma, then epithelial healing will be delayed until new stroma can be built via
recruitment of granulation tissue from the nearest available vascular bed: the limbus. After a lag of about four days,
a combination of new vessels and fibroblasts will the begin to grow from the limbus at approximately 1 mm per day.
Although the blood vessels will become less prominent over time, and the haphazard fibroblasts will become
oriented parallel to the corneal epithelial surface, such granulation tissue will never completely disappear and will
always be clinically and microscopically distinguishable from normal stroma. It is claimed that injured corneal
stroma will thus never be remodeled with the extremely precise architecture required to insure perfect corneal
clarity.

Complications of corneal wound healing include the following:

Keratomalacia: liquefactive necrosis of corneal stroma as a bystander effect of neutrophilic inflammation.

Ordinarily, it is a sequel to bacterial or fungal contamination.

Descemetocele: Outward bulging of Descemet’s membrane through a defect created by corneal stromal necrosis of
any pathogenesis

Iris prolapse: protrusion of iris through a full thickness in defect in corneal epithelium, stroma, and Descemet’s
membrane. Occasionally seen as a sequel to a gradually deepening ulcer, it is more often encountered as in instant
sequel to full thickness corneal perforation.

Persistent ulcer (recurrent erosion, Boxer ulcer): failure of proper epithelial: stromal adhesion leading to persistent
or recurrent shallow ulceration. There is no apparent defect in epithelial proliferation, or in production of adhesion
molecules. The defect probably lies in the superficial corneal stroma, which seems unable to properly anchor the
hemidesmosomes.

Corneal facet: focal corneal epithelial thickening as a consequence of purely epithelial healing of a shallow corneal
defect that included the superficial stroma.

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Corneal sequestrum: devitalization of the corneal stroma secondary to ulceration. Most commonly seen in cats, in
which the dead stroma acquires a characteristic brown/black discoloration, the same histologic phenomenon occurs
in dogs and in horses with persistent ulcers. The dead stroma becomes acellular and is usually surrounded by a thin
zone of lytic neutrophils. The lesion is slowly extruded through the corneal surface, in step with gradual corneal
stromal turnover.

Corneal epithelial downgrowth: as far as we know, the corneal epithelium is not particularly intelligent. It will grow
along a suitable stromal scaffold, wherever that scaffold happens to lead! Occasionally, following a perforating
corneal injury (including a surgical incision), the corneal epithelium will grow down the “cut edge” of the stromal
scaffold. It may gain access to the anterior chamber and grow over the surface of iris, through the pupil, etc.
Alternatively, the epithelium can be implanted into the stroma and grow as an epithelial inclusion cyst.

Corneal Inflammation
Theoretically, since the cornea is an avascular tissue, it cannot undergo inflammation. Nonetheless, the
nomenclature of “keratitis” is widespread in the clinical literature even though many of the syndromes included
under that name are probably not truly inflammatory. Leukocytes will gain access to the cornea from any break in
the continuity of the surface epithelium, or will migrate from the limbal blood vessels in response to any pathogens
that are permitted to colonize the corneal stroma. The significance of the leukocytes within the stroma is related
almost entirely to the development of bystander stromal injury from granulocytic enzymes, and the production of
leukocyte-associated growth factors that will stimulate corneal vascularization and scarring. Although in general the
histology of keratitis has no special features that are distinct from inflammation in other tissue, there are a few
specific entities that are worth mentioning:

Feline eosinophilic keratitis: an idiopathic ulcerative and superficial stromal keratitis in which eosinophils
predominate. In old lesions, or in those heavily treated with steroids, plasma cells predominate and the eosinophils
may be very few. The disease is usually diagnosed by cytologic examination of corneal scrapings. Because the
disease is often chronic/treated by the time the scraping is done, it is important to remember that one eosinophils in a
feline cornea is one too many, and justifies the diagnosis! A histologically indistinguishable lesion will occasionally
occur in conjunctiva, without apparent corneal involvement.

Equine mycotic keratitis: although occasionally seen in other species as opportunistic overgrowth within a
devitalized superficial corneal stroma, deep stromal mycotic keratitis is almost exclusively of disease of horses. The
disease is probably always secondary to chronic antibiotic and/or steroid administration for some otherwise-
harmless traumatic corneal ulceration. The histologic lesion is distinctive: a deep stromal suppurative keratitis in
which the neutrophils are always karyorrhectic. They are most numerous adjacent to Descemet’s membrane, and the
fungi are also found in greatest numbers adjacent to, or within, Descemet’s membrane. In many cases, this is the
only location in which they can be found (an important consideration when you are attempting to evaluate the utility
of corneal scrapings or superficial keratectomies in the diagnosis of this disease). Because the lesion is chronic and
deep, there is frequently healing of the overlying stroma and epithelium, creating a deep-seated stromal “abscess”.
From a clinical perspective, getting medication to this deep infection then becomes problematic and usually requires
therapeutic superficial keratectomy. Despite the fact that the fungi may cause lysis of Descemet’s membrane and
may have a neat into the anterior chamber, they seem unable to grow within the globe except when in contact with
Descemet’s membrane. There is, in other words, no apparent risk of mycotic endophthalmitis.

Pannus: Also known as pannus keratitis, this is a slowly progressive, often bilateral lesion affecting German
Shepherd dogs and many other breeds, particularly those that are “shepherd-like” in body phenotype. The histologic
lesion is distinctive, and bears great histologic similarity to the cutaneous lesions of discoid lupus: interface
plasmacytic keratitis with basal cell injury, pigmentary incontinence and superficial stromal scarring with
vascularization. The disease is always bilateral but not necessarily symmetrical. Its prevalence, rapidity of
progression, and eventual severity are correlated with sunlight exposure.

Corneal endothelialitis: usually seen in concert with anterior uveitis, the corneal endothelium may be an apparently
specific target for neutrophilic or mononuclear infiltration. The result is transient or even permanent corneal edema.
The cause for the specific endothelial targeting in most naturally occurring examples is not known, but
experimentally there may be cross-reaction between corneal endothelium and infectious disease antigen that makes

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the corneal endothelium an accidental target for immune attack. Alternatively, viral infection of that endothelium
may result in persistent viral antigen that becomes the target for antibody (immune complex disease) or cellular
attack.

Corneal cutaneous metaplasia

An extremely common corneal reaction to any persistent low-grade external irritant, we see cutaneous metaplasia in
chronic keratoconjunctivitis sicca, any improper eyelid configuration, exophthalmos, or ocular enlargement
secondary to glaucoma. In short, any disease of gradual onset that requires the cornea to become “tougher” will
cause the cornea to recall its cutaneous embryologic heritage. It is worthwhile remembering that many of the same
injuries, if applied quickly or with greater severity, will cause corneal “decompensation” and will result in
ulceration. There are numerous clinical synonyms for this phenomenon of corneal cutaneous metaplasia:
desiccation keratitis, exposure keratitis, pigmentary keratitis, etc.

The histologic hallmarks of this cutaneous metaplasia include some or all of the following: epithelial hyperplasia
and keratinization, epithelial or stromal melanin pigmentation, thickening of the basement membrane with
development of rete ridges, superficial stromal fibrosis, and stromal vascularization. All of these changes are
reversible and are probably reflections of changes that originate within the permanent replicative population of
epithelial stem cells at the limbus. These are the cells that retain unlimited mycotic capability, and act as the lifelong
stem cells for both conjunctival and corneal epithelium. Since all of these histologic changes do not necessarily
occur in every example, I presume there are different stimuli and chemical messengers for each of these events. It
seems reasonable to assume that corneal cutaneous metaplasia is not actually an active process by which the corneal
epithelium and stroma become skin-like, but rather a process by which the pluripotential limbal stem cells fail to
express the specialized phenotype of cornea.

Retrocorneal fibrous membrane: Although the mature corneal endothelium is said to be in the capable of mitotic
replication (it will repair defects via sliding, but not replication), it seems to acquire substantial proliferative capacity
when it undergoes fibrous metaplasia. Following such injuries as lens luxation or massive external trauma, the
normally inconspicuous endothelium proliferates as fibroblast-like cells. They are distinguished from true
fibroblasts by the retention of PAS-positive basement membrane production. The cells may be restricted to this
“fibrous” plaque lining the cornea, but the cells may also migrate across the filtration angle to grow on the anterior
surface of iris, caused pupillary block, or enter the posterior chamber. In at least some instances, it is difficult to
determine whether all of the fibrous membrane has originated from corneal endothelium, or whether it has received
contributions from deep corneal stromal fibroblasts or from cells growing out of the iris stroma.

Other Corneal Lesions

Lipid keratopathy: the deposition of lipid, usually as cholesterol, within the corneal stroma is a relatively common
observation in corneas with chronic inflammation. It also occurs without pre-existing inflammation as a
consequence of abnormal dietary lipid profiles, in animals with metabolic lipid abnormalities, and as poorly-
characterized primary corneal “lipid dystrophy”. Cholesterol crystals are found within the subepithelial corneal
stroma. In most cases, they eventually stimulate a mild granulomatous inflammatory reaction.

Corneal mineralization: mineralization of basement membrane and subepithelial stroma occurs commonly in dogs.
It is seen in puppies as transient lesion of unknown pathogenesis, and it occurs with characteristic clinical features in
a variety of breeds that have inherited stromal “calcific” dystrophies.

Bullous keratopathy: secondary to profound corneal stromal edema, there is percolation of the edema fluid from the
stroma outwardly into the corneal epithelium where it becomes temporarily trapped as bulla between adjacent
epithelial cells.

UVEA
The uvea (iris, ciliary body and choroid) is formed by a combination of neurectoderm and mesenchymal stroma. It
is a highly vascularized tissue that shows a range of general pathology responses indistinguishable from any other

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“ordinary” tissue. Yet even here there are some unique features, related mostly to the initiation of inflammation and
to its consequences. But first, a few points of anatomy and physiology that are important in determining the
significance of uveal disease to the rest of the globe.

Firstly, the normal iris lays against the face of the lens, moving back and forth in response to autonomic stimuli.
Any exudation that makes the iris sticky greatly increases the risk of iridolenticular adhesion (posterior synechia).
In turn, this increases the risk of pupillary block, thus leading to iris bombe and secondary glaucoma. Iridocorneal
adhesion (anterior synechia) is much less frequent and is seen almost exclusively as a consequence of perforating
corneal injury.

Secondly, there are no tight junctions along the anterior border layer of the iris. The blood: eye barrier is at the level
of corneal vascular endothelium. Thus, any leukocytes or fluids that exude from the iris vessels almost immediately
enter the aqueous humor. Conversely, any chemicals within the aqueous humor will have free access to the iris
stroma. This is relevant because one rarely sees a heavy accumulation of edema or granulocytes within the iris, even
when there is a massive accumulation within the aqueous humor. It also explains the great frequency with which we
see preiridal fibrovascular membranes, responding to growth factors circulating within the aqueous humor from sites
of production elsewhere within the globe. Conversely, the blood vessels within the ciliary processes are freely
permeable, and the blood: eye barrier exists at the level of tight junctions between adjacent ciliary epithelial cells. It
is thus common to see marked distention of ciliary processes with edema during the early stages of inflammation, as
the fluid is easily able to exude through the vessels, but not through the ciliary epithelium.

Serous effusion (from inflammation or from vascular hypertension) from the choroid has the unique consequence of
causing retinal detachment, which in turn leads to photoreceptor degeneration because photoreceptor health requires
intimate apposition between the photoreceptors and the cell membrane of the retinal pigmented epithelium. Within
hours of such separation, the RPE undergoes characteristic hypertrophy. Light microscopic detection of
photoreceptor degeneration takes days to weeks, depending on the magnitude of the separation and character of the
fluid.

Helpful hint: the presence of RPE hypertrophy is very useful when attempting to distinguish genuine retinal
detachment from artifact. The presence or absence of photoreceptor degeneration can often be used to estimate the
duration of that detachment.

Thirdly, the anterior urea is very sensitive to inflammatory stimuli originating within the cornea. There are both
neural and chemical pathways by which even mild corneal irritation increases vascular permeability within the iris,
resulting in exudation of proteinaceous fluid into the normally protein-poor aqueous (so-called aqueous flare).

Fourthly, the iris is susceptible to the development of preiridal fibrovascular membranes. Angiogenic growth factors
released from detached retina, from intraocular neoplasms, or as a consequence of chronic inflammation anywhere
within the globe are absorbed into the iris stroma and act, apparently by accident, on the iris blood vessels. These
stromal vessels and accompanying fibroblasts grow outwardly onto the anterior face of the iris. From that location,
there is a definite risk of migration to cause occlusion of the filtration angle or pupillary block.

And finally, the accumulation of inflammatory exudate within the posterior chamber and the vitreous tends to
organize by fibrous metaplasia and to contract into a transverse band that extends from ciliary body across the globe
to the other ciliary body. This is thus a retrolenticular fibrous membrane known as a cyclytic membrane. It will
usually incorporate the detached retina into its posterior face.

The Nomenclature of Uveitis

Anterior uveitis: iridocyclitis.

Panuveitis: inflammation of iris, ciliary body, and choroid.

Endophthalmitis: panuveitis plus inflammatory exudate within the anterior chamber, posterior chamber, and vitreous
cavity (note: in histologic sections, almost all diseases that have been clinically characterized as anterior uveitis or
some other type of uveitis are histologically classified as endophthalmitis).

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Panophthalmitis: endophthalmitis that has progressed to involve the sclera. Almost all such cases are bacterial.

Hyalitis: at least in theory, inflammation limited to the vitreous.

The Causes of Uveitis

The causes of uveitis include all of the familiar systemic infectious diseases, which require no elucidation here.
They have the same histologic hallmarks within the globe as they would in any other tissue. The ones we see most
frequently vary by species and somewhat by geography. In dogs, the common uveal infectious diseases include
blastomycosis, cryptococcosis, erlichiosis and Rocky Mountain spotted fever, and coccidioidomycosis.
Blastomycosis is by far the most common. In cats, the list is dominated by cryptococcosis and FIP. As in every
other body system, toxoplasmosis always appears on the differential list but is virtually never proven! In cattle,
virtually the only proven infectious uveitis is malignant catarrhal fever.

More frequent, and much more puzzling, are the many non-infectious causes of uveitis. The most prevalent among
these is a histologically uniform but etiologically diverse group that we gather under the broad umbrella of
lymphonodular anterior uveitis. Perivascular accumulations of lymphocytes and plasma cells are found within iris
and ciliary body, and occasionally within choroid. No infectious agent is seen. We assume that such lesions
represent “immune-mediated “ uveitis, but our understanding of the exact pathogenesis is rudimentary. Equine
recurrent uveitis is probably the best studied of this group, with epidemiologic evidence that cross-reaction between
leptospiral antigens and intraocular antigens plays an important role. In cats, most of the attention has focused on
toxoplasma as the cause, but in fact there is no proof. In the three species most often affected (dog, cat, and horse),
the lesions are not only histologically similar but the clinical course of recurrent episodes of intractable uveitis tends
to be very similar. As pathologists, we see the disease only in the advanced stages when it has progressed to
glaucoma or when it has exhausted the owners’ patience or bank account. In cats, and perhaps in horses, the lesions
are correlated with the development of glaucoma by some unknown mechanism. Oddly, this does not happen in
dogs.

The other important, non-infectious examples of uveitis are uveodermatologic syndrome ( Vogt-Koyanagi-Harada)
and lens-induced uveitis. The former is exclusively canine, while the latter is encountered in virtually every species
including fish and birds.

The VKH-like syndrome is a bilateral, granulomatous, destructive endophthalmitis that seems to target melanin-
containing cells throughout the uveal tract. It is particularly destructive of the RPE, but will also affect the
pigmented iridociliary epithelium. It has a predilection for the Akita and various “arctic” breeds. It has a presumed
immunologic basis. The ocular disease is substantially more frequent than the skin disease, and most dogs with
ocular lesions do not have the concurrent granulomatous interface facial dermatitis.

Lens-induced uveitis is divided into phacoclastic and phacolytic uveitis. They differ substantially in pathogenesis,
clinical significance, and histopathology. Phacolytic uveitis is something that a pathologist would rarely see. It is
described as a mild lymphocytic anterior uveitis in response to the leakage of denatured lens protein from
hypermature cataracts. It usually responds well to medical management, and would virtually never be a cause for
enucleation. It does not appear to involve an immunologic pathogenesis, since researchers have been unable to
demonstrate that these tiny denatured lens proteins are immunogenic.

Conversely, phacoclastic uveitis is a severe destructive suppurative and granulomatous endophthalmitis that occurs
as a delayed response to the rupture of a previously normal lens. The sudden presentation of all this lens protein to
the immune system overwhelms of the low-dose tolerance to lens protein, and results in a severe inflammation that
is initially suppurative and then granulomatous. The disease is typically delayed for ten days to several weeks after
lens injury, and requires that the lens capsular rupture be large enough to allow the escape of a substantial amount of
lens protein. There appear to be substantial species differences, with rabbits and birds undergoing a more classical
granulomatous response than is true of dogs or cats. As important as the initial granulomatous inflammation are the
delayed events of attempted lens repair. Those events involve migration and fibrous metaplasia of lens epithelium.
That epithelium, when it escapes from the lens through the capsular defect, is able to proliferate extensively within
the globe. It will cause pupillary block, occlusion of the filtration angle, and even migration into the vitreous. In

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cats, it undergoes malignant transformation and we believe it is the tissue of origin for the so-called post-traumatic
ocular sarcoma that is unique to cats.

Helpful hint: Remember that most cases of phacoclastic uveitis involved penetrating ocular trauma, and there is a
very real risk of sepsis. Many examples of phacoclastic uveitis have concurrent septic endophthalmitis.

LENS
While the clinical diseases of lens are quite important, the histopathology of lens is incredibly boring: a cataract is a
cataract is a cataract! With very rare exceptions that involve the presence of some foreign material or specific
infectious agent within the lens, one learns nothing about the pathogenesis of the cataract by looking at its histology.
The most important task for the histopathologist is to distinguish frequent lens artifacts from “the real thing”. The
lesions of cataract are those of hydropic swelling of lens fibers, liquefaction of cortical fibers, and the proliferative
consequences of attempted lens repair. The degenerative changes include the formation of spherical globules of
hypereosinophilic lens protein known as Morgagnian globules. These are the single most reliable indicators of
genuine cataract. Artifactual fragmentation of lens fibers creates ragged rectangular brick-like fragments, never
spherical globules.

The normally inconspicuous lens epithelium, which is found only under the anterior lens capsule, undergoes
posterior migration, hypertrophy and hyperplasia as futile efforts at lens repair. The proliferating cells often fall
victim to the same degenerative change that caused the original cataract, and undergo marked hydropic change to
create the so-called “bladder cells” which are also reliable (but not invariable) indicators of cataract.

Helpful Hint: the normal lens contains no leucocytes. The observation of even a single leukocyte within the lens
means that, somewhere, there has been lens capsule rupture.

RETINA
Whereas the study of uveal disease is dominated by the study of inflammation, the study of retinal disease is
definitely dominated by non-inflammatory degenerative disease related to maldevelopment, detachment, ischemic
injury, toxic and metabolic photoreceptor disease, and glaucoma. While retina certainly undergoes a variety of
inflammatory diseases as part of generalized endophthalmitis or as an extension of central nervous system disease,
inflammatory disease that is unique to retina is very rare
.
The nomenclature of retinal disease is a nomenclature of neuropathology, and I will not dwell on it further. The
retina is populated by ganglion cells, astrocytes, axons, and other routine neural elements. It does, however, have a
few anatomic features that are very important to the proper interpretation of retinal lesions.

Firstly, the retina lies in apposition to the RPE, but there are no firm attachments. Any degeneration in the
gelatinous vitreous, effusion from the choroid, or traction from organizing vitreal inflammation will easily cause
“tractional” retinal separation, which has profound influences on photoreceptor health.

Secondly, in common domestic mammalian species, the inner half of the retina is nourished by the intrinsic retinal
vasculature. The outer half of the retina, including the outer nuclear layer and the photoreceptors, receives its
nutritional support (nutrient delivery and waste removal) from the RPE and choroid.

Thirdly, the neural elements within the mature retina (the age of maturation varies with the species; in dogs and cats
the peripheral retina matures at about six weeks of age) are incapable of replication/regeneration. Photoreceptors
can be rapidly reconstituted, but not if t their cell bodies within the outer nuclear layer have been destroyed.

Helpful Hint: for the study of retinal disease, rapid fixation with something other than routine formalin is almost
essential. Bouin’s fixative is an excellent choice, but there are several other acid-based fixatives that are
acceptable. If formalin is the only practical choice, suggest the intravitreal injection of 0.25-0.5 ml of formalin
prior to immersion of the naked globe in fixative.

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General Approach to the Interpretation of Retinal Degenerative Disease:
1. Count the layers! The hallmark of almost all retinal degenerative disease that you will see is a loss of one or
more nuclear layers. It makes a huge difference whether the missing layer is the photoreceptor and/or outer
nuclear layer, or nerve fiber and ganglion cell layer. As a very important rule of thumb, the only disease to
selectively destroy inner retina is glaucoma. All of the toxic and metabolic retinal diseases affect the
photoreceptors and, when chronic, the cells of the outer nuclear layer.

2. Is there any geographic variation/specificity? Many of the degenerative diseases specifically target dorsal vs.
ventral retina, or central vs. peripheral retina. Some will specifically target cones, while others habitually affect
the rods.

3. Is the RPE spared or affected? In most retinal diseases, the RPE remains normal. If the RPE is also injured, it
is a valuable clue suggesting that the retinal disease may be a sequel to previous chorioretinitis or to vascular
disease.

4. Is the retinal disease tidy and zonal, or is it multifocal, random, and messy? Virtually all of toxic and metabolic
photoreceptor diseases caused diffuse photoreceptor atrophy that is very specific, leaving other retinal elements
virtually untouched. In contrast, retinas damaged by vascular or inflammatory disease will have changes of
multifocal gliosis, irregular blending of nuclear layers, and migration of pigment-laden cells derived from RPE
even if there are no persisting leukocytes.

Selected Retinal Diseases

Hypertensive retinopathy
Another example of a disease that did not exist...until we looked! The changes are found within blood vessels
anywhere within the eye, but probably are most commonly appreciated within the retinal blood vessels. Small
arterioles become thickened with edema and sometimes with fibrinoid change. In long-standing cases there may be
muscular hypertrophy. There is perivascular hemorrhage or the accumulation of hemosiderin, and there may or may
not be ischemic degenerative changes within the tissue supplied (actually, not supplied!) By these vessels. Retinal
detachment secondary to the leakage of fluid into the subretinal space is common.

Retinal dysplasia
Although this is directly translated as disordered retinal development, it is a confusing concept because the retina
continues to develop afterbirth, and disordered development can be induced by in utero or postnatal infectious
disease as well as by inborn developmental errors. Examples caused by infection, usually viral infection, will have
changes of patchy gliosis, pigmentary migration, and scarring identical to changes seen in the adult retina with
similar infectious disease. In addition, however, there will be futile attempts at retinal regeneration, and the
hallmark is retinal rosettes. These are tubular/acinar accumulations of primitive photoreceptors.

In the hereditary retinal dysplasia of purebred dogs, there are none of these other degenerative retina lesions, and the
only change is abnormal retinal maturation. There are few too many retinal rosettes, but in this instance they are
almost always just transverse sections through tubes of folded retina. Although there continues to be much debate,
my own opinion is that they should not be called retinal dysplasia because it is really only improperly regulated
retinal growth, not defective retinal structure. The retina folds on itself, but it has no actual disorganization. In
some instances, the folds disappear as the globe grows!

Retinal detachment
Retinal detachment may occur secondary to a retinal tear with subretinal seepage of liquefied vitreous, secondary to
organization and traction of a vitreal inflammatory exudate, or by serous effusion secondary to choroidal
inflammation or vascular hypertension. Detachment will also occur as one outcome of marked ocular enlargement
secondary to glaucoma. The sequels of retinal detachment include rapid hypertrophy of the RPE, and more gradual
degeneration of photoreceptors, followed by outer nuclear layer. The inner nuclear layer and ganglion cells will not
be affected in those species that have an intrinsic retinal vasculature. The detached retina is an important source for
angiogenic growth factors, and is a the most common cause for preiridal fibrovascular membrane.

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GLAUCOMA
More than half of the globe you will receive will be from animals with intractable glaucoma. While there have been
great strides made in the medical and surgical treatment of that common disease, the truth remains that you can
enucleate early, or spend a lot of money and then enucleate later! Money delays the inevitable, but it does not
prevent it. Glaucoma is of such importance in veterinary ophthalmic pathology that it deserves this special section.

Definitions:
glaucoma: the clinical syndrome attributable to a pathologic elevation in intraocular pressure
primary glaucoma: glaucoma arising from a developmental error in the formation of the outflow pathway. Although
the lesion is developmental, the onset of clinical disease is usually delayed for several years

secondary glaucoma: glaucoma arising in a previously normal eye, secondary to the obstruction in the outflow
pathway.

goniodysgenesis: malformation of the filtration angle, including any portion of the trabecular meshwork, the
pectinate ligament, or the scleral outflow pathways.

Causes:
Dogs: more than half the cases are primary glaucomas (one of the great crimes of purebred dog breeding). Although
one can detect goniodysgenesis, it is also true that the risk of eventual glaucoma cannot be directly core related with
the prevalence of the goniodysgenesis. It appears to act as a marker for the increased risk, but the histologic lesion
that we are able to detect may not be the direct cause. This remains of very hot topic in veterinary ophthalmology
circles.

Causes of secondary glaucoma include pupillary block from posterior synechia, lens luxation that permits anterior
prolapse of the vitreous to cause pupillary block, direct occlusion of the trabecular meshwork by intraocular
neoplasia, and the formation of fibrovascular membrane secondary to intraocular tumor or chronic retinal
detachment.

Cats: the leading causes of glaucoma in cats are lymphonodular uveitis and diffuse iris melanoma, in almost equal
proportions. Other causes are so infrequent that they do not count! The goniodysgenesis, thanks to random
breeding, is rare. The mechanism by which lymphonodular uveitis causes the glaucoma remains a complete
mystery.

Horses: once thought to be a very rare disease, glaucoma has emerged as a relatively frequent, underdiagnosed
condition in this species. Like everything else equine, they seem to “do it differently”. Most horses with glaucoma
have no histologic explanation for the development of the glaucoma. Clinical claims that these horses all have had
previous bouts of uveitis are difficult to substantiate by histologic assessment.

Histologic lesions secondary to glaucoma (listed in approximate order of prevalence):

• inner retinal atrophy
• optic nerve atrophy
• optic disk cupping
• megaloglobus/scleral thinning
• angle recession (cats)
• exposure keratopathy
• corneal striae (horses)

9
PERIOCULAR OPHTHALMIC SURGICAL PATHOLOGY

Although the pathology of the globe itself is usually viewed as more intriguing and certainly more intimidating, the
working diagnostic pathologist is likely to see many more examples of eyelid, scleral, and conjunctival disease than
of enucleated globes. The problem is that the realm of periocular surgical pathology now contains a seemingly
endless array of specific clinical/pathologic syndromes. Although the syndromes may seem very similar in
histologic features, some of the subtle difference may carry profound significance in terms of prognosis and therapy.
It is no longer adequate for a pathologist to offer a correct “general pathology” description and interpretation. We
must enter the world of the clinical ophthalmologist, and be prepared to offer a clinically and therapeutically
relevant diagnosis.
Well, you may be willing, but how do you get there from here? Virtually all textbooks suffer from the same “catch
22” problem: you cannot read about a lesion or disease unless you already know what it is! When viewed from the
pragmatic perspective of day-to-day diagnostic pathology, and especially in a specialized area like ocular pathology,
this convention seems to have little to justify it. In these notes we have tried to organize the material so that it is laid
out in the same problem-solving hierarchy that we ourselves use: exactly where is the lesion, is it inflammatory or
neoplastic, and does it match any specific disease syndrome? In addition, the eye has a uniquely direct structure-
function correlation so that virtually every histologic lesion will have a functional consequence and, almost
certainly, will have had a clinically detected counterpart. More than in any other area of pathology, the ocular
pathologist must correlate the microscopic lesions with the clinical findings, reconstruct a plausible sequence of
events (because, in the eye, one lesion almost always will cause other lesions to develop elsewhere in the eye), and
help establish a prognosis for the affected or even for the opposite eye.

Step One: Where is the lesion?

Most ocular syndromes have site predilections, sometimes so strong that identical lesions in different sites have very
different biologic significance and may even have different names. Perhaps the best example is melanoma, in which
tumors arising in different anatomic sites or in different species have radically different prognoses.

Step Two: Is it inflammatory, proliferative, or unequivocally neoplastic?

Most of us will have little difficulty dealing with the cut-and-dried extremes of this spectrum, but ophthalmic
pathology is perhaps uniquely littered with nebulous “proliferative” diseases of unknown cause. Most of them
respond to immunosuppressive therapy and are thus temporarily sheltered under the broad umbrella of so-called
immune-mediated disease.

Step Three: Do the lesions explain the clinical observations?

A disciplined ophthalmic pathologist never finishes a case until he/she attempts to find a microscopic lesion to
explain each clinical observation or functional abnormality.

Step Four: Do the microscopic lesions, patient profile, and clinical features combine to
match a described clinical syndrome or specific etiology?
This is the most difficult step, requiring that every ophthalmic pathologist also be at least part clinician! The general
diagnostician will often be correct in description and morphologic diagnosis, only to fail miserably in assigning the
correct “final”diagnosis because he/she fails to connect the histologic lesion to a specific clinical entity that may be
defined as much by location, clinical progression or even breed as by microscopic character.
Now for the sample...

10
So you have an EYELID biopsy?
If it is neoplastic,...
a) sebaceous proliferation = Meibomian adenoma
b) basal cell proliferation = probable Meibomian adenoma, check for even a hint of sebaceous differentiation
c) well-pigmented benign melanoma
d) squamous cell carcinoma
e) any skin tumor (histiocytoma, schwannoma, mast cell tumor)

If it is proliferative but not neoplastic,...

a) sheet of epithelioid macrophages = chalazion (polarize)
b) papillary squamous nodule at lid margin = epithelial hyperplasia overlying Meibomian adenoma
c) coalescence of suppurating granulomas = granulomatous marginal blepharitis

So you have a CONJUNCTIVAL biopsy?

If it is neoplastic,
a) intraepithelial cell nests, epithelioid = malignant melanoma
b) spindle cells with channel formation = hemangioma/sarcoma
c) squamous cell carcinoma

If it is inflammatory,...
a) subepithelial lymphoid aggregates = lymphonodular conjunctivitis
b) perivascular/diffuse lymphoplasmacytic = nonspecific chronic conjunctivitis
c) eosinophilic perivascular with edema = presumed allergic conjunctivitis
d) granulomatous, without discrete granulomas or collagenolysis = nodular
granulomatous episcleritis (lymphocytes, fibroblasts)
e) granulomatous, lid margin, suppurating = marginal granulomatous blepharitis
f) coalescing lipid lakes with mild granulomatous reaction in the palpebral conjunctiva of a cat = idiopathic
lipogranulomatous conjunctivitis (probably, of feline version of chalazion)

So you have a THIRD EYELID biopsy?

If it is neoplastic,...
a) typical adenocarcinoma = carcinoma of the gland of the third eyelid
b) malignant lymphoma (cats, occasionally horses, cattle)
c) squamous cell carcinoma (in this site, especially horses)
d) hemangioma, angiokeratoma, hemangiosarcoma
e) resembling fibrous histiocytoma = probable nodular fasciitis/NGE

If it is inflammatory,...
a) garden variety conjunctivitis
b) proliferative, nodular mixture of mononuclear leucocytes, fibroblasts = nodular granulomatous episcleritis

11
So you have a LIMBAL biopsy?
If it is neoplastic,...
a) heavily pigmented, within limbal sclera = benign limbal melanoma
b) junctional activity, lightly pigmented, spreading = conjunctival malignant melanoma
c) hemangioma, angiokeratoma, hemangiosarcoma
d) squamous cell carcinoma

If it is inflammatory,...
a) subconjunctival nodule created by random intermingling of mononuclear leucocytes and fibroblasts without
discrete granulomas = nodular granulomatous episcleritis
b) deeper sclera, collagenolytic (sometimes eosinophilic) granulomas, invasive = necrotic scleritis

So you have an ORBITAL biopsy?

If it is inflammatory,...
a) diffuse, no apparent target, suppurative = orbital cellulitis secondary to tooth abscess, foreign body
penetration, rarely from panophthalmitis
b) lymphocytic interstitial lacrimal adenitis, often with marked atrophy
c) ocular lymphocytic myositis, lymphocytic and atrophic

If it is neoplastic,...
a) adenocarcinoma = lacrimal carcinoma if dorsolateral, from zygomatic salivary gland if ventral. Rare
examples of nasal carcinoma, metastatic carcinoma.
b) nondescript spindle-cell sarcoma
c) multilobular osteochondrosarcoma
d) lymphoma
e) neuroblastoma

12
Glossary of common periocular ophthalmic syndromes

Adenocarcinoma of the gland of the third eyelid: very old dogs, slowly invasive, well differentiated adenocarcinoma
with frequent squamous metaplasia. Occurs, rarely, in cats.
Angiokeratoma: conjunctival hemangioma growing in lobules among prominent pseudocarcinomatous epithelial
down growths.
Chalazion: bland nodular granulomatous inflammation around a Meibomian gland. Most often seen adjacent to
Meibomian adenomas. The epithelioid macrophages contain brightly polarizable crystals.
Conjunctivitis, eosinophilic: conjunctival hyperemia, edema, and perivascular eosinophils. Assumed to reflect
allergy.
Conjunctivitis, lymphocytic lichenoid: see Plasmoma.
Conjunctivitis, lymphonodular: multiple subepithelial lymphoid aggregates below what often is conjunctival
squamous metaplasia. Garden-variety chronic conjunctivitis with no etiologic implications.
Dacryoadenitis: usually lymphocytic interstitial inflammation of lacrimal or nictitans gland, often with atrophy and
squamous metaplasia.
Fibrous histiocytoma: see Nodular Granulomatous Episcleritis
Granulomatous marginal blepharitis: coalescing, suppurating granulomas under the conjunctiva of the lid margin.
The lesion may initially be solitary, but most cases are described as either coalescing or diffuse, unilateral or
bilateral. Same type of lesion is occasionally seen elsewhere in conjunctiva. It occurs, rarely, in cats. No agent has
been seen or grown.
Hemangioma, hemangiosarcoma: occurs with equal prevalence on margin of third eyelid or in lateral bulbar
conjunctiva, predilections suggesting an actinic causation. The lesions reflect a continuum from histologically
benign to malignant, but metastasis has not been reported. Wide excision is curative. Very rare in cats. In horses,
often quite solid and may be mistaken for fibrosarcoma.
Lacrimal adenocarcinoma: typical adenocarcinoma, specificity comes from site in dorsolateral orbit. Little reported
about behavior, but most are advanced and inoperable by the time of diagnosis.
Meibomian adenoma: easily the most prevalent eyelid tumor in dogs. Virtually all are benign, but considerable
phenotypic variation includes sebaceous hyperplasia, sebaceous epithelioma, and basal cell tumor with scant
sebaceous maturation. Often these are pigmented, and are accompanied by overlying papillary epidermal
hyperplasia and underlying chalazion.
Melanoma, conjunctival: epithelioid, often poorly pigmented, behaviorally malignant with local invasion and
eventual metastasis in cases with inadequately aggressive surgery. Strong histologic similarities to the spectrum of
oral melanomas, and very different from the other ocular melanomas (eyelid, limbal, uveal and choroidal). Dogs
and, occasionally, cats.
Melanoma, eyelid: similar to ordinary skin melanoma in dogs, virtually always benign, discrete, well pigmented. In
cats, uncommon but more aggressive in appearance and behavior.
Melanoma, limbal: benign, heavily pigmented melanoma arising within the limbal sclera from the row of
melanocytes that demarcate the corneoscleral junction. May expand outward into conjunctival sac, but never inward
into the globe. Usually arises at dorsolateral limbus (sunlight?). Rare in cats, but does occur.
Necrotic scleritis: see Scleritis, necrotic.
Neuroblastoma, retrobulbar: rare but incredibly aggressive primitive tumor seen in young dogs. Volume may double
weekly, with rapid invasion through optic foramen into brain. Origin is unknown (Ganglioneuroblastoma?
Anaplastic chemodectoma?)
Nodular fasciitis: see Nodular granulomatous episcleritis.

13
Nodular granulomatous episcleritis: common steroid-responsive proliferative lesion of dogs, affecting limbal
conjunctiva/episclera and, occasionally, other conjunctival sites. Histologically similar lesion affects bulbar aspect of
third eyelid, often bilaterally, with strong predilection for collies. Microscopic lesion represents a spectrum, but
ingredients are intermingled lymphocytes, macrophages and fibroblasts without necrosis, without suppuration, and
without formation of discrete granulomas. Collie lesion is more purely proliferative (“fibrous histiocytoma”).
Papilloma, eyelid margin: true papillomas are uncommon, and viral papillomas in this site are rare. The common
lesion is papillary epithelial hyperplasia overlying Meibomian adenomas.
Plasmoma: a truly appalling clinical name for a lichenoid lymphoplasmacytic conjunctivitis with marked leucocytic
accumulation that creates a clinically thickened conjunctiva. May be conjunctival variant of pannus keratitis, with
same breed predilections.
Prolapse of the gland of the third eyelid (haws, cherry eye): histologic lesions are secondary to partial strangulation
and desiccation, with marked edema accounting for most of the perceived enlargement of the gland.
Orbital cellulitis: sequel to penetrating foreign body, tooth root abscess, meningitis. Specific localized syndromes of
presumed immune pathogenesis occur, with targeting of lacrimal gland (lymphocytic interstitial adenitis) or
extraocular muscles.
Scleritis, necrotic: unilateral or bilateral spreading destructive lesion that begins near limbus and invades caudally.
Microscopic lesion is coalescence of collagenolytic granulomas, sometimes with prominent eosinophils.
Distinguished in biopsies from similar lesions of nodular granulomatous episcleritis by the presence of
collagenolysis and at least some true granulomas.
Spindle cell tumor, retrobulbar: as controversial as cutaneous spindle cell tumors, most are of unproven origin.
Microscopic spectrum resembles hemangiopericytoma, schwannoma, meningioma, fibrosarcoma, etc. Delayed
diagnosis and difficult surgical site require cautious prognosis, but no good data.
Squamous cell carcinoma: most diagnoses are obvious. Species and site predilections related to sunlight exposure.
Rarity in dogs is unexplained. Metastasis only if chronically neglected.

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Ocular Tumors
More than half of all the samples you will receive will be of suspected neoplasia, so it is easy to justify spending
substantial time on this one subject. What is written below is a fairly simple, sensible review of the various tumors
by location.

A. Tumors of the haired eyelid

1. Meibomian adenoma
By far the most frequent eyelid tumor of dogs, this is an almost-exact replica of the very common sebaceous
hyperplasia / adenoma as it occurs in ordinary skin. It consist of variable proportions of basal cells and mature
sebaceous cells that ordinarily form coalescing lobules reminiscent of normal Meibomian / sebaceous glands,
with some central squamous metaplasia resembling normal sebaceous ducts. It is not seen in other domestic
species.
The tumor occurs as a flask-shaped nodule along the lid margin, which is the location of the normal Meibomian
gland. Most examples are easily recognized as coalescing sebaceous lobules, different from normal Meibomian
gland because of a relatively greater proportion of germinal basal cells, less regular lobular architecture, and
much greater overall mass. Unlike sebaceous hyperplasia / adenoma in ordinary skin, Meibomian tumors
routinely have a marked increase in the relative proportion of basal cells, and often contain melanin pigment.
The near-perfect architectural fidelity seen in cutaneous sebaceous hyperplasia is rarely seen in Meibomian
tumors, which therefore look like better candidates for genuine neoplasia than do many of the cutaneous
sebaceous “adenomas”.
Many examples have bland granulomatous inflammation (chalazion, see below) surrounding the tumor, and
have papillary epithelial hyperplasia of the overlying lid margin. Either of these changes may be more obvious
than the underlying Meibomian adenoma.
Genuine behavioral malignancy is exceedingly rare. Some tumors that are particularly rich in basal cells may
have substantial mitotic activity, but they exhibit no peripheral invasion. There are so few documented examples
of truly malignant behavior that one would need overwhelming histologic evidence to justify a diagnosis of
Meibomian adenocarcinoma.

2. Eyelid melanoma
Melanomas arising from the haired skin of the eyelid are histologically and behaviorally identical to
melanomas arising elsewhere in skin. Thus, in dogs they are heavily pigmented and are almost invariably
benign, whereas in cats about 50 percent of them are histologically and behaviorally malignant.
These eyelid melanomas do not merit any discussion that is different from what is appropriate to melanomas
elsewhere in skin. It is important to distinguish whether the melanoma is originating from the haired skin or
from the palpebral conjunctiva, for reasons that are analogous to the similar distinction that must be made at the
oral mucocutaneous junction. Those arising from the non-haired conjunctival epithelium are substantially more
dangerous than those originating from the haired skin. As with oral melanomas, their behavior cannot be
predicted by traditional histologic criteria of malignancy (see Conjunctival melanoma).
The typical canine eyelid melanoma consists of heavily pigmented epithelioid melanocytes that grow in
intimate contact with the surface epithelium and usually have intraepithelial nests of tumor cells. Nuclear
variation is minimal and mitotic figures are usually absent. The cells may be arranged in nerve-like clusters,
endocrine-like nests, or as swirling slender spindle cells that are distinguished from other spindle cell tumors
only because of the presence of cytoplasmic melanin.
In cats the cells tend to be less pigmented, and those examples that are destined for behavioral malignancy have
the usual criteria of anisokaryosis, increased mitotic figures, and invasive growth habit that are typical of feline
cutaneous malignant melanomas elsewhere.

15
 Eyelid melanomas in horses are apparently rare. They may occur in gray horses as part of the generalized
melanosis syndrome, or sporadically in any horse. Those reported have been behaviorally benign.

3. Eyelid squamous cell carcinoma

Squamous cell carcinoma arising within the haired skin of the eyelid is almost exclusively a feline phenomenon
( see below for a detailed discussion of conjunctival squamous cell carcinoma in cattle and horses). It occurs
almost exclusively in white cats exposed to the carcinogenic effects of sunlight, and may occur concurrently
with squamous cell carcinoma of the nasal skin and ear pinnae. It goes through the usual progression of actinic
epidermal necrosis with dysplastic repair, and stepwise transition through carcinoma-in-situ to outright
invasive squamous cell carcinoma.
Even within the same specimen the histology may be regionally variable and often includes preneoplastic and
fully developed malignant change. There is epidermal ulceration with substantial accompanying inflammation,
and dysplastic epithelial repair that involves hyperchromasia, jumbling, and anisokaryosis within the expanded
basal layer. Transition to outright carcinoma is characterized by failure of maturation, by increasing cytologic
atypia with traditional nuclear criteria of malignancy, and most importantly by invasion of immature epithelial
cells (often resembling stratum spinosum cells) into the underlying dermis. There routinely is a marked
lichenoid lymphocytic-plasmacytic inflammatory response, assumed to be triggered by altered tumor antigens.
Lesions are often extensive along the eyelid margin, frequently becoming bilateral and virtually circumferential
unless halted by surgical intervention.

4. Squamous papilloma
Proliferative lesions clinically diagnosed as “papillomas” are most often regions of papillated epithelial
hyperplasia overlying Meibomian adenomas. Foci of papillary hyperplasia, without cytologic atypia, will
occasionally occur independent of any underlying neoplasm and are of unknown pathogenesis. Genuine viral
papillomas, with histologic features identical to viral papillomas elsewhere in skin or in mouth, have been
reported but the actual prevalence is probably very low.
The usual lesion occurring at the eyelid margin is a pedunculated localized papillated hyperplasia of otherwise
normal squamous epithelium overlying a Meibomian adenoma. Squamous papillomas, occurring independently
of Meibomian tumors, most frequently effect the bulbar conjunctiva. They create multiple slender papillae of
hyperplastic but orderly stratified squamous nonkeratinized epithelium supported by a delicate fibrous stalk.
Such lesions lack any of the viral cytopathic effects so typical of viral papilloma.

5. Chalazion
Although clearly not a neoplasm, chalazion is frequently mistaken for neoplasia on clinical examination, and is
thus submitted as a tumor for histologic evaluation. The characteristic lesion is a collection of bland
vacuolated macrophages around an inflamed or (more commonly) neoplastic Meibomian gland. We assume
that the lipid secretion from the abnormal gland is leaking into the surrounding dermis to trigger this reaction.
The macrophages have innumerable cytoplasmic crystals that polarize with a characteristic white birefringence
that is different from the more yellow birefringence of the surrounding collagen. Some chalazia also contain
large lakes of lipid that could be mistaken for dilated lymphatics or even lymphangioma.
Most chalazia are almost purely granulomatous, with much less of the suppurative or lymphocytic components
that commonly accompany leakage of sebaceous gland tumors elsewhere in skin.

6. Miscellaneous skin tumors occurring within the eyelid

Any skin tumor can occur within the eyelid, but those occurring with perhaps greater than usual frequency
include benign cutaneous histiocytoma in dogs, mast cell tumor in cats, sarcoid in horses, and schwannoma in

16
 various species. None has any special histologic character that distinguishes its eyelid manifestation from its
typical histologic appearance elsewhere.

B. Tumors of the conjunctiva and third eyelid

1. Squamous cell carcinoma

Squamous cell carcinoma affecting the sunlight-exposed, non-pigmented epithelium of the bulbar conjunctiva
and third eyelid is common in cattle and horses living in appropriate climates and under appropriate
management practices. Tumor prevalence is correlated with altitude and mean hours of sunlight exposure. The
tumor goes through a series of pre-cancerous changes involving actinic injury and dysplastic repair prior to
malignant transformation, giving rise to a temporal sequence of lesions that have been called squamous
plaque, squamous papilloma, squamous carcinoma in situ, and invasive squamous cell carcinoma.
This continuum is identical to what occurs with sunlight-induced cutaneous squamous cell carcinoma in other
locations. The developing tumor is marked by ever-increasing nuclear pleomorphism, hyperchromasia, and
maturational jumbling within the epithelium. In many instances, increasingly convincing malignant change
within the epithelium is accompanied by a lichenoid infiltration of lymphocytes and plasma cells that may be a
manifestation of immune surveillance. The mature tumor consists of a thick jumbled layer of cells generally
resembling stratum spinosum, with marked anisokaryosis, hyperchromasia, and mitotic figures no longer
restricted to the basal layer. Invasion of these atypical cells across the basement membrane into adjacent lamina
propria is the important criterion distinguishing carcinoma-in-situ from full-fledged squamous cell carcinoma.

2. Conjunctival melanoma
Melanomas arising within the basal layer of the conjunctival epithelium are described in dogs and in cats.
These generally occur as pleomorphic epithelioid melanomas with poor pigmentation, abundant junctional
activity, and clinically aggressive behavior.
They resemble oral melanomas in terms of the range of phenotypic disguises that, in the absence of
pigmentation, can make precise identification difficult. They usually grow as solid endocrine-like packets of
20-30 cells defined by a delicate fibrous stroma. The cells generally have abundant eosinophilic cytoplasm that
may be finely granular. As is typical of malignant melanomas elsewhere, there may be substantial variation
from this classical appearance. Mononuclear gigantism with hyperchromatic convoluted nuclei is a frequent
variation, as is loss of the endocrine-like packeting in favor of diffuse sheets of round-to-polygonal cells that
give little clue as to their melanocytic origin. In such cases, substantial reliance must be placed on the
conjunctival origin and the paucity of realistic alternative diagnoses. Pigment, when present, is most often
found in those tumor cells that are within and near the epithelium. Intraepithelial clusters (junctional activity)
are routinely present in those biopsies that have been oriented to successfully capture that conjunctival
epithelium. As is true with the histologically similar oral melanomas, the tumor cells may not show many of the
traditional cytologic criteria of malignancy. Criteria like anisokaryosis, hyperchromasia, and high mitotic index
are not necessarily present in tumors that, retrospectively, have shown invasive and even metastatic behavior.

3. Hemangioma, angiokeratoma and hemangiosarcoma

These endothelial tumors are characterized by the accumulation of thin-
walled vascular channels within the conjunctival lamina propria. These channels coalesce to create blood-
filled masses that obliterate pre-existent architecture, with adjacent channels separated only by a mature
fibrous stroma without identified pericytes or smooth muscle. They form a continuum of cytologic maturity,
with those lined by inconspicuous bland normochromic endothelium being classified as hemangiomas, and
those formed by hyperchromatic endothelium with at least moderate anisokaryosis classified as

17
 hemangiosarcomas. In dogs, this distinction appears to have no behavioral significance in that all are
behaviorally benign and surgically curable; in horses, however, there is a distinctive solid hemangiosarcoma
involving the third eyelid that is a behaviorally aggressive malignancy.
Angiokeratoma is a histologic variant of hemangioma, in which hyperplastic downgrowths from the overlying
conjunctival epithelium insinuate themselves among the vascular channels, serving to separate the vascular
channels into “nodules” within the superficial lamina propria
Vascular tumors arising within the conjunctival lamina propria are seen primarily in dogs, horses, and very
rarely in cats. In dogs, they occur with about equal frequency below the bulbar conjunctiva of the temporal
limbus and along the leading edge of the third eyelid, suggesting that sunlight exposure is an important
contributing factor in their consists. About 1/3 of cases are bilateral. Most examples are traditional capillary
hemangiomas-to-hemangiosarcomas, with histologic features identical to those vascular tumors more
commonly found in the dermis.
In horses, most of the few cases described have been on the bulbar surface of the third eyelid near its free
margin. A few occur in the temporal bulbar conjunctiva. Most of the published third eyelid tumors have been
locally invasive, solid spindle cell tumors in which the endothelial cells only occasionally separate to form
identifiable vascular channels. Numerous lymphocytes are scattered amid the interstitium. It is likely that
many of these atypical hemangiosarcomas would be mistakenly diagnosed as fibrosarcoma by those not familiar
with the existence of this distinctive equine variant. Horses also develop “ordinary” hemangiomas and
hemangiosarcomas identical to those seen in dogs. It is unclear whether these more traditional tumors behave in
a manner different from the solid “fibroblastic” hemangiosarcomas.

4. Adenocarcinoma of the gland of the third eyelid

Well-differentiated and slowly growing tubular and acinar adenocarcinomas, often with abundant squamous
metaplasia, are rare tumors of the third eyelid of very old dogs (mean age at diagnosis is 11 years).
These uncommon tumors present little diagnostic challenge. They form jumbled and moderately invasive
clusters of neoplastic tubules lined by cuboidal, columnar, or squamous epithelium. The only possible confusion
would be with dysplastic repair following inflammatory injury to this gland (this gland, like the lacrimal gland
itself, commonly suffers from a destructive, idiopathic lymphocytic interstitial adenitis leading to
keratoconjunctivitis sicca). These low-grade carcinomas generally have an regionally invasive habit and will
almost always recur if the surgical approach is anything less than removal of the entire third eyelid. Metastasis
has not been reported, but the number of described cases is still small. A similar tumor is occasionally seen in
cats.

5. Malignant lymphoma
Malignant lymphoma may infiltrate the retrobulbar tissue, the uveal tract, the conjunctiva, or the eyelid in the
course of generalized malignant disease. There are sporadic reports of malignant lymphomas that appear to
have arisen within the lamina propria of the third eyelid in animals that do not (yet?) have disseminated
disease.
These do not differ in histologic phenotype from lymphoma found elsewhere, but it takes considerable courage
to make this diagnosis when the tumor is apparently present only in this single, unlikely location.

6. Nodular granulomatous episcleritis (nodular fasciitis, nodular granulomatous

episclerokeratitis, ocular fibrous histiocytoma)
As is implied by the plethora of alternative names for this lesion, there has been (and continues to be)
considerable debate about how many different diseases share this same histologic appearance, and whether
differences in clinical appearance or anatomic location justify separating these into multiple separate

18
 diagnostic entities. The consensus among those pathologists particularly interested in eyes is that this should,
for the moment, be considered a single entity.
The clinical lesion is a smooth, pink, proliferative protruding mass apparently arising within the conjunctival
lamina propria at the limbus, posterior to the limbus, or even within the palpebral conjunctiva. Lesions may be
bilateral. The histologic lesion is a nodular accumulation of uniformly intermingled lymphocytes, histiocytes
and fibroblasts without the formation of discrete granulomas.
The relative proportion of each cell type varies from case to case, and probably varies over time even within the
same lesion. The various names that have been used reflect our confusion about whether this represents one
entity or several. We have chosen to group them together because the similarities far outnumber the differences.
Most lesions are composed predominantly of macrophages, lymphocytes and plasma cells, with no
collagenolysis and very few granulocytes of any type. The proliferation is predominantly within the
conjunctival lamina propria, creating a nodule that has no encapsulation but which has a relatively well
circumscribed growth habit. No etiologic agent has ever been detected. None of the cells shows any
convincing malignant phenotypic changes. This common canine lesion is included here because its
macroscopic appearance is of a “tumor”. Its successful control by various immunosuppressive therapeutic
agents places it somewhere in that gray zone of “immunoproliferative disease” that plagues ocular and
cutaneous surgical pathology!

7. Miscellaneous tumors and proliferative lesions

a. Corneal / conjunctival inclusion cyst

Embedded within the superficial corneal stroma or within the adjacent bulbar conjunctiva, these cysts are lined
by stratified squamous epithelium and contain greater or lesser amounts of keratin debris. Those derived from
conjunctival epithelium may have some goblet cells within the wall.
Some are developmental errors and represent nests of superficial ectoderm entrapped by accident within the
mesenchyme that forms the conjunctival lamina propria and corneal stroma. Most, however, are the result of
accidental implantation of surface epithelium as a consequence of surgical incisions or accidental penetrating
injuries.

b. Conjunctival papilloma
These are non-viral pedunculated lesions of unknown cause. They consist of focal papillated hyperplasia of
conjunctival epithelium, protruding from either bulbar or palpebral conjunctiva.
The surface epithelium may retain a perfect conjunctival phenotype that includes goblet cells, but more often
the epithelium has undergone squamous metaplasia. Each papilla is supported by a slender fibrovascular stalk
indistinguishable from conjunctival lamina propria. There is no cytologic or histologic atypia suggesting
impending progression to squamous cell carcinoma, and there are none of the cytopathic effects typical of
papillomavirus infection. These lesions are not related to the so-called squamous papillomas that are precursor
lesions of actinic conjunctival squamous cell carcinoma in horses and cattle.

c. Mast cell tumor

Mast cell tumors, histologically identical to those occurring in haired skin, occasionally occur within the
conjunctival lamina propria, especially, within the third eyelid. There is insufficient follow-up information to
provide any guidance about whether grading criteria validated for cutaneous mast cell tumors can be applied
in this context. There is no published information about postoperative biological behavior.

19
C. Tumors of the orbit

The bones, nerves, vessels and other soft tissues within the orbit may give rise to any of the bony or soft tissue
neoplasms as described in other body systems. There is little point in listing the many tumors that have been
described (often only once!) within the orbit just because they happen to have occurred there. We limit our
discussion to those tumors which seem to have some predilection for the orbit.

1. Retrobulbar spindle cell tumors

a. Optic nerve meningioma

Although there is no widespread agreement among pathologists interested in ophthalmic pathology, many feel that
most orbital spindle cell tumors are indeed meningiomas. The problem is that the histologic range for meningioma
is so broad that it is virtually impossible to exclude meningioma as a diagnosis for any orbital spindle cell tumor in
the vicinity of the optic nerve. Given the limited space within the orbit, any sizable tumor will sooner or later find
itself “within the vicinity” of the optic nerve! That being said, there are undoubtedly tumors of the orbit that meet
all of the traditional criteria for meningioma.

b. Other retrobulbar spindle cell tumors

As is true in other tissues, the precise histologic identification of retrobulbar spindle cell tumors is a nightmare of
imprecision because histopathology simply cannot distinguish among the many candidates for tissue of origin.
There are reports of orbital rhabdomyosarcoma, meningioma, hemangiosarcoma, liposarcoma, schwannoma,
granular cell tumor, hemangiopericytoma, fibrosarcoma, and fibrous histiocytoma. Few of these reports are
substantiated by electron microscopy or immunohistochemistry, and most are represented by just one or two
examples.
I know of no association between any specific diagnosis and subsequent behavior; the orbit is a difficult surgical
target and these tumors usually are quite advanced by the time the initial diagnosis is confirmed. Metastasis seems
to be rare.

2. Lacrimal adenoma and adenocarcinoma

Tumors arising from the retrobulbar lacrimal gland resemble those arising from the anatomically and
embryologically similar salivary glands. Almost all reported examples have been behaviorally aggressive
adenocarcinomas. They generally are quite well differentiated, with easily recognized tubular and acinar
maturation. The cuboidal-to-columnar epithelial cells usually retain abundant cytoplasmic vacuolation typical
of normal salivary / lacrimal epithelium fit
When faced with an orbital glandular neoplasm, the only significant decisions to be made are whether the tumor
is behaviorally benign or malignant, and whether it originates from the lacrimal gland or from the zygomatic
salivary gland that lies on the anterior and ventral floor of the orbit. The first decision (benign vs. malignant) is
usually not difficult because most lacrimal tumors show unequivocal invasion into surrounding normal tissues,
even if they retain reasonably good cytologic maturation. Distinction from the rare zygomatic tumors is based
primarily on location. The lacrimal gland is located in the dorsal-lateral quadrant of the orbit just posterior to
the sclera. The zygomatic gland is ventromedial.

3. Multilobular tumor of bone (multilobular osteoma, multilobular osteochondroma, multilobular

osteochondrosarcoma, chondroma rodens and others)
The suture lines among the bones that form the orbit represent one of the predilection sites for this uncommon,
slowly expanding neoplasm that has had many different names over the years. The currently most common
name of osteochondrosarcoma is in recognition that a substantial proportion of the untreated tumors will
eventually metastasize. The tumor arises from the aponeuroses between adjacent flatbones, with a particular

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 predilection for the canine skull. The tumor occurs only rarely in cats, and there is a single (non-orbital) report
from a horse.
The histologic appearance of the orbital tumor is the same as for this tumor in other locations: a coalescence of
multiple islands of bone, cartilage, and osteoprogenitor spindle cells separated from one another by distinct
fibrous trabeculae, creating a multilobular appearance when examined at low magnification. The classical tumor
nodule enclosed within these septa consists of spindle-shaped mesenchymal cells that produce eosinophilic-to-
basophilic extracellular matrix that matures into unequivocal chondroid. and the mesenchymal cells themselves
will mature into recognizable chondrocytes in association with the most mature matrix. Bone formation seems
to occur directly from the non-chondroid mesenchymal cells, but some bone also forms from maturation of the
cartilage. Even within the same tumor there often will be great variation in the relative amounts and maturity of
the mesenchymal, cartilaginous, and osseous components. The most reliable criterion for diagnosis is the
distinctive lobular architecture that is not shared by any other bone tumor. Histologic criteria for malignancy
are seldom obvious, and it is not clear whether those tumors that eventually metastasize have gradually acquired
a more malignant phenotype, or whether all of these tumors harbor such malignant potential.

4. Neural and neuroendocrine tumors

Every collection of orbital pathology will contain a few unclassified non-lymphoid round cell tumors that have
been tentatively diagnosed as chemodectoma or as neuroblastoma. In general these tumors have been very
rapidly progressive tumors in young dogs of larger breeds, causing exophthalmos and invasion through optic
foramen into brain. Because the cellular origin or precise differentiation of these tumors has not been proven,
such cases do not get published. They are included here only so that colleagues will be alerted to the presence
of these extremely aggressive tumors as a distinct syndrome. Their proper classification is a “work in
progress”!
The histologic appearance of such tumors is of small hyperchromatic round-to-polygonal cells that frequently
are arranged in solid clusters of 15-30 cells by a very delicate fibrous stroma. Mitotic figures are extremely
numerous (seeing an average of at least 10 in every 40x field is common).

5. Tumors reaching the orbit by regional invasion or metastasis

Tumors may reach the orbit by direct extension from adjacent tissues, or from vascular metastasis. Orbital
invasion by oropharyngeal, sinus and nasal tumors should theoretically be a relatively common event, but we
rarely encounter such tumors because few animals are permitted to progress to this degree of neoplastic
invasion. Orbital invasion from a primary ocular tumor is surprisingly rare, probably because there are few
primary intraocular tumors that possess such invasive potential (feline ocular sarcoma being a notable
exception).
Any neoplasm undergoing systemic metastasis can theoretically lodge and grow within the orbit, but the only
one to do so with any frequency is malignant lymphoma in cattle.

PRIMARY INTRAOCULAR TUMORS

A. Melanoma

Taken across all species, neoplastic proliferation of uveal melanocytes is the most common of all ocular tumors. As
with melanomas elsewhere, there is substantial variation in biological behavior depending upon species and precise
location. These site / species variables are more important to prognosis than are the many histologic and cytologic
variations.

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1. Canine anterior uveal melanoma (melanocytoma)
This is the most common primary intraocular tumor of dogs. They are a remarkably uniform group, arising from
the melanocytes within the stroma of the iris or ciliary body. They ordinarily form a solid, deeply pigmented mass
that protrudes into the anterior or posterior chamber. Growth is expansive rather than invasive, even when that
“expansion” includes migration of tumor cells along normal aqueous drainage pathways. Because these pathways
are normally populated by resident melanocytes, the spread of tumor into the limbic sclera (following the
corneoscleral drainage pathway) or into peripheral choroid (the uveoscleral drainage pathway) does not require
that the tumor cells violate any genuine tissue barriers. Such extension should not be considered true invasion and
it is not predictive of metastasis.
The typical tumor has an inconspicuous germinal population of plump spindle cells with a central oval nucleus,
minimal variation in nuclear size or staining, and very few mitotic figures. This germinal population often
represents less than 5 percent of the total tumor population; most of the cells are ballooned “plump cells” distended
with pigment. These cells are assumed to represent post-mitotic endstage melanocytes.
Although growth is usually as a single expansive mass protruding into one of the ocular chamber, some example
will remain localized within the anterior uvea and will grow in a circumferential fashion to virtually fill the anterior
uvea.
The prognosis for these very common tumors has been greatly misunderstood. In contrast to human uveal
melanomas, these canine tumors have virtually no metastatic potential. The rare case that is destined to undergo
metastasis (about 5 percent) can be identified on the basis of mitotic index, although such tumors often have other
histologic criteria of malignancy like anisokaryosis, hyperchromasia, and genuinely invasive, destructive intraocular
growth. A mitotic index in excess of 3 per 40x field has, in retrospect studies, been associated with metastasis.

2. Canine choroidal melanoma

Rarely one encounters a melanoma within a canine globe that is identical to an ordinary anterior uveal melanoma
except that it arises from melanocytes within the choroid.
These typically are extremely slow growing, expansive masses that eventually bulge into vitreous. Those few cases
reported have been completely benign in cytologic phenotype and in behavior, although eventually their large size
would be expected to cause retinal detachment or optic nerve compression. Metastasis has not been described.

3. Canine diffuse uveal melanosis

There is a distinctive clinical entity described in Cairn terriers as pigmentary glaucoma, which involves a diffuse
proliferation of anterior uveal melanocytes that, in our opinion, are indistinguishable from those of more traditional
anterior uveal melanoma. The growth habit is habitually diffuse, involving even the choroid, and is typically
bilateral. Occlusion of the trabecular meshwork results in glaucoma.
In my judgment, this proliferative disease has all the features of neoplasia (uncontrolled proliferation of a
monotypic, atypical cell type) and we see no reason not to include it here. We assign it a separate designation only
because of its clinically distinct presentation. It will occasionally occur in breeds other than Cairn terriers. Because
these cells are not substantially different from normal melanocytes, it can be a difficult diagnosis in some heavily
pigmented breeds like black Labrador retrievers and Kerry Blue terriers. The distinction is purely quantitative, with
the normal-appearing melanocytes occupying the trabecular meshwork and causing a choroidal thickening beyond
the range for normal melanocytes.

4. Feline diffuse iris melanoma

Seen clinically as unilateral coalescing hyperpigmentation of the iris that slowly progresses to diffuse iris thickening
and secondary glaucoma, this is a uniquely feline presentation of a diffuse, pleomorphic melanoma affecting
primarily the iris stroma.

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The tumor originates from the layer of melanocytes that forms the anterior border layer of the normal iris. These
cells develop nuclear enlargement and hyperchromasia, and slowly proliferate to replace the normal iris architecture.
Such proliferation usually occurs over a period of years, although the rapidity of progression is highly variable. The
fully developed tumor, as the name implies, results in a diffuse iris (and often, ciliary) infiltration by pleomorphic
round-to-epithelioid melanocytes. The cytologic phenotype is extremely variable, but we know of no prognostic
significance to any of these variables. Tumors very from amelanotic to heavily pigmented, and from round cell to
epithelioid to spindle cell (and mixtures of all of the above!). Mononuclear gigantism is frequently seen.
The prognosis has been the subject of great debate over the past 10 years. Retrospective studies that have attempted
to establish histologic predictors of behavior have been thwarted by poor overall follow-up data (cats lost to follow-
up, very few necropsies). Nonetheless, emerging from these studies is the general consensus that, while these are
substantially more likely to eventually metastasize than are canine uveal melanomas, the overall risk that an affected
cat will die from its melanoma is less than 20 percent. Predictors of metastasis include invasion into sclera and / or
posterior iris epithelium, and large overall tumor size. The general recommendation is to watch these tumors for any
sudden change in growth habit, but not to perform immediate enucleation unless necessitated by tumor-induced
glaucoma. All of these tumors will eventually cause glaucoma, but that progression may take 5-7 years (during
which time the cat should be left with both eyes!).

5. Feline multifocal uveal melanoma

Very occasionally, one encounters a tumor within the feline anterior uvea that looks histologically identical to
canine anterior uveal melanoma: a nodular tumor protruding into the ocular chambers, dominated by heavily
pigmented, endstage “plump cells” and with an inconspicuous germinal spindle cell population. These are
sufficiently different from the usual diffuse iris melanoma to justify a separate classification.
In the only published paper describing this entity, the tumor seemed to arise from multiple foci throughout the reveal
tract, expanding into the ocular cavities but also outwardly into sclera. There is no good information about the risk
of metastasis.

6. Intraocular melanomas in non-carnivores

Melanomas resembling canine benign anterior uveal melanomas are occasionally encountered within the anterior
uvea of horses, cattle, and other species. They are rare and there are no collected behavioral data.

B. Iridociliary adenoma and adenocarcinoma (Ciliary body adenoma and

adenocarcinoma, ciliary body tumor)

These are relatively common intraocular tumors in dogs (second in prevalence only to melanoma). They are
occasionally seen in cats, but they are infrequent in other species. They arise from the mature neurectoderm that
forms the bilayered epithelium covers the posterior surface of the iris and the ciliary body (tumors of the embryonic
neurectoderm are discussed under Medulloepithelioma). They are grouped together because they represent a
continuum of histologic differentiation, and because even those tumors that look like unequivocal malignancies
based upon traditional histologic criteria virtually never metastasize. In the entire world literature there are only
two credible, individual case reports of iridociliary tumors that have metastasized. Thus, spending a lot of
intellectual effort in trying to distinguish adenoma from adenocarcinoma is pointless because the gold standard for
malignancy (metastasis) is so infrequent.
The typical tumor is a well differentiated papillary adenoma that creates a oval-to-spherical mass that protrudes into
the posterior chamber. The cells are cuboidal-to-columnar epithelial cells similar to normal ciliary epithelium, and
most tumors continue to produce abundant PAS-positive basement membrane material similar to that made by
normal ciliary epithelium. Some are pigmented, but the presence or absence of pigment has no significance except
to cause confusion (both clinically and histologically) with uveal melanoma. More primitive examples are solid
tumors made up of nondescript cuboidal epithelium, sometimes creating a jumbled mass of cells that could be
mistaken for metastatic lymphoma or even a primitive amelanotic melanoma. As mentioned above, some examples

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have all the traditional histologic criteria for malignancy including anisokaryosis, hyperchromasia, mononuclear
gigantism, and increased mitotic activity. These are not proven to be of any behavioral significance when dealing
with this highly tissue-specific tumor that presumably is unable to survive in any other environment. The retention
of basement membrane production is a valuable ally in making the diagnosis in these primitive examples.
Ciliary body tumors usually grow as solitary nodules into the lumen of the posterior chamber. Occasionally, they
invade through the posterior iris epithelium and occupy the iris stroma or even the anterior chamber itself. We do
not know whether those tumors exhibiting this iridal invasion are those that originate from the iris epithelium or not.
About half of the tumors have extension along perivascular spaces of the scleral venous plexus (as do many benign
melanomas), but this is probably not true invasion.
Distinguishing poorly differentiated iridociliary adenocarcinoma from adenocarcinoma metastatic into the globe can
be difficult. The presence of abundant thick PAS-positive basement membrane material is highly conserved by most
iridociliary tumors and is a valuable clue. Although not routinely needed, selected cases may benefit from
immunohistochemistry. Ciliary body tumors (like normal iridociliary epithelium) are almost always positive for
vimentin and neuron-specific enolase, which are not likely to be encountered in any other epithelial neoplasm.

C. Medulloepithelioma

These uncommon, histologically distinctive neoplasms are most often reported in horses, and indeed they are the
most frequent primary ocular neoplasms in that species. They are by definition congenital tumors, although clinical
recognition may be delayed for several years. They are derived from the embryonic neurectoderm lining the inner
layer of the optic cup, and may show differentiation into any of the derivatives of that pluripotential tissue:
iridociliary epithelium, retina, vitreous, and neuroglia.
They may be found growing into the vitreous body from their origin anywhere along the ciliary body o rretina. The
typical neoplasm consists mostly of hyperchromatic cuboidal or round cells reminiscent of primitive retinal
neurectoderm, forming a loose papillary network somewhat reminiscent of primitive ciliary processes. The
epithelium frequently forms tubular rosette-like structures in which the tumor neuroblasts cluster around a central
cavity. These primitive neuroblasts, whether in cords or in rosettes, rest upon a prominent basement membrane
analogous to the inner limited membrane of retina. On the other side of that membrane is a myxoid matrix
analogous to primitive vitreous.
Although the formation of these neoplastic rosettes is the characteristic feature, many tumors consist primarily of
diffuse sheets of primitive neoplastic cells with only a few such rosettes. Especially in horses, these tumors may
contain foci of muscle, bone, cartilage, or even brain tissue and are thus classified as teratoid medulloepitheliomas.
Metastasis has not been reported.

D. Iridociliary cysts (iris cysts)

Fluid-filled cysts arising by failure of fusion, or subsequent separation, of the two layers of neurectoderm covering
the posterior aspect of the iris or the inner aspect of the ciliary body are relatively common in dogs and can be
confused, clinically, with intraocular melanomas.
These cysts may be solitary or multiple, adherent or free-floating. They most commonly seem to represent failure of
apposition between the two layers of pigmented epithelium lining the back of the iris. The cyst wall is formed by
attenuated cuboidal epithelium, and the lumen is either empty or contains some granular eosinophilic debris.

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E. Feline primary ocular sarcoma (post-traumatic sarcoma)

The aggressive and uniquely feline tumors are pleomorphic intraocular spindle cell sarcomas that, even within the
same tumor, may include phenotypes reminiscent of fibrosarcoma, chondrosarcoma, osteosarcoma, or giant cell
tumor of soft tissue.
These enigmatic tumors are unique to cats, despite ample opportunity for them to be observed in other species that
have suffered massive ocular trauma. All published cases, and almost all of the cases within our unpublished
collections, have occurred in globes that have suffered previous trauma that includes lens rupture (including surgical
lens “rupture” as part of cataract surgery). The interval between trauma and detection of tumor can be many years,
but the key word here is “detection”. We do not know the rapidity of microscopic tumor development following
injury.
The earliest tumors can be seen originating from the spindle cells proliferating adjacent to a site of lens capsule
rupture, but in most specimens submitted for histologic examination the tumor virtually fills the globe. We
speculate that the tumor arises from lens epithelium that, after escaping through a capsular rent, undergoes
fibroblastic anaplasia and (in an unknown percentage of cases) malignant transformation.
The neoplasm habitually grows circumferentially within the posterior chamber and vitreous, initially serving to “line
the globe” with a thick layer of tumor rather than growing into the vitreous cavity as a mass. These tumors
frequently invade the optic nerve and then the orbit and brain. Although capable of distant metastasis, clinical signs
related to invasion into brain through the optic nerve are the most frequent cause for postoperative euthanasia. At
the moment, there seems little prognostic / therapeutic justification for any attempt to subclassify these tumors to
reflect the expression of fibroblastic, osteoblastic, chondroblastic, or other phenotypic maturations.

F. Optic nerve glioma

There are several reports of astrocytoma or undifferentiated “glioma” affecting the optic disk, particularly of
horses. Most of these reports predate the era of immunohistochemistry, and in retrospect most of these cases
probably reflect proliferation of astrocytes and lipid-laden macrophages as a consequence of optic nerve damage
(i.e. proliferative optic neuropathy).
There is no theoretical reason why optic nerve and even retina should not occasionally develop glial tumors as do
other portions of brain, but proven examples are elusive.

G. Tumors metastatic within the globe

Because the globe is not frequently examined as part of routine necropsy (or even routine clinical examination!),
estimates of the overall prevalence of metastatic disease within the globe probably are grossly inaccurate. All one
can say is that it is not at all unusual to discover metastatic foci within the eyes of animals with disseminated
malignancy.
Undoubtedly the most prevalent tumor metastatic within the globe is malignant lymphoma, but that may reflect only
its position as the most common metastatic tumor that we would encounter in almost every species that we are likely
to examine. As for the others, all we can say is “look and you shall find!”. Another relatively common metastatic
tumor is hemangiosarcoma, but its apparent frequency may be related to its habit of causing intraocular hemorrhage.
It may thus have an unfair advantage over other tumors in terms of attracting attention.
Within the globe, tumors may be found as emboli within uveal or retinal blood vessels. Carcinomas, in particular,
tend to grow out of those vessels and to form a layer of malignant cells on the surface of the iris and ciliary body as
if growing within a tissue culture chamber. Since this growth habit is not typical of primary iridociliary tumors or

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uveal melanomas, it helps distinguish metastatic carcinoma from the occasional example of a poorly differentiated
primary intraocular neoplasm.

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