The uvea

BACKGROUND AND NON-NEOPLASTIC DISEASES

Normal anatomy

Anterior uvea: iris and ciliary body

Iris (Fig. 9.1)

Figure 9.1.

Normal anterior uvea. (A) Low magnification photomicrograph of the normal canine iris and irido-corneal angle structures. (B) Low magnification of the normal equine iris and irido-corneal angle structures including the corpora nigra (arrow). (C) Higher magnification of a normal canine iris showing the iris epithelium and dilator muscle. (D) Low magnification of the canine iris and irido-corneal angle from a normotensive dog with goniodysgenesis. (E) The highly muscular iris from a diving bird (Loon). In birds, the iridal muscle is skeletal muscle, and in this diving bird the robust iris muscle is important in accommodation. It plays a role in increasing the curvature of the anterior lens surface, thereby increasing refraction. (F) Low magnification of a canine iris with a blue eye showing the absence of melanin in the stroma even though the posterior pigment epithelium is fully pigmented.

• •
  Stroma

  • ▪
    Embryologically derived from the neural crest, apart from vascular endothelium derived from mesoderm
  • ▪
    Loose connective tissue stroma populated by fibroblasts and melanocytes. Melanocyte population tends to be more dense in the posterior stroma than in the anterior stroma
  • ▪
    The anterior border has no epithelial surface and, therefore, there is little to deter fluid exchange with the anterior chamber
  • ▪
    Capillaries are non-fenestrated, contributing to the ‘blood-aqueous barrier’. However, blood vessel endothelium lacks tight junctions in many domestic animals, with permeability differing greatly between species

    • –
      Inflammation of the iris leading to increase in vascular permeability manifests as protein in the aqueous humor. This is detectable by slit-lamp biomicroscopy as ‘aqueous flare’
  • ▪
    The iris stroma, and for that matter the entire globe, lacks lymphatic vessels
• •
  Muscles and posterior epithelium

  • ▪
    Sphincter muscle

    • –
      Constricts in bright light and during accommodation
    • –
      Smooth muscle in mammals, derived from neuroectoderm of optic cup
    • –
      Striated muscle in birds and most reptiles, in which it is predominantly of neural crest origin
  • ▪
    Dilator muscle and posterior pigmented epithelium

    • –
      The posterior epithelium and the dilator muscle together form a complex two-layered structure derived from the neuroectoderm of the anterior optic cup
    • –
      The posterior, pigmented epithelium of the iris is continuous posteriorly with the inner, non-pigmented epithelium of the ciliary body
    • –
      The myoepithelial cells of the anterior iris epithelium are among the most complex cells of the body. Basally, their cytoplasm is contractile (the dilator muscle) and apically the cytoplasm of these epithelial cells contains melanin granules. The anterior iris epithelium is continuous with the pigmented epithelium of the ciliary body
    • –
      In birds and most reptiles, as with the constrictor muscle, the dilator muscle is striated, although smooth muscle often also plays a role in pupil dilation
  • ▪
    Granula iridica (corpora nigra)

    • –
      In domestic herbivores such as equidae, bovids, and camelids, the iridal epithelia at the superior margin of the pupil, and sometimes also at its inferior margin, gather and expand anteriorly to form prominent pigmented nodules or, in the case of the New World Camelids, well-organized pleats
    • –
      The postulated role of the granula iridica is to shade the structures of the inner eye from ambient sunlight from above, much like the bill or visor of a baseball cap

Ciliary body (Fig. 9.2)

Figure 9.2.

Normal ciliary body. (A,B) Photomicrographs of the canine ciliary body pars plicata showing the inner non-pigmented epithelium, the pigmented epithelium, and the zonular ligaments (arrows). (C) Canine ciliary body epithelium, stained with Alcian blue PAS, showing the secretion of hyaluronic acid in blue. (D) Dissecting microscope image of the canine lens suspensory apparatus showing normal zonular ligaments. The formalin-fixed globe was post-fixed in glacial acetic acid, which helps to opacify the zonular ligaments fibers (arrows).

• •The ciliary body is continuous anteriorly with the base of the iris. The structure and function of the aqueous outflow pathways will be addressed in Chapter 13, given their importance in the pathology of glaucoma
• •The ciliary body is divided into an anterior pars plicata, characterized by a series of meridional folds or processes, from which the suspensory zonules of the lens originate, and a posterior pars plana. The structure of the ciliary processes, in terms of their topography and angio-architecture differs considerably between mammalian species, and in non-mammalian vertebrates distinct ciliary processes may be absent
• •
  The stroma and the ciliary muscle

  • ▪
    The supraciliary space is a potential space between the sclera and ciliary body and is continuous posteriorly with the suprachoroidal space. The supraciliary and suprachoiroidal space play a role in the uveoscleral or unconventional pathway of aqueous outflow. This space becomes prominent when exudates or hemorrhage accumulate in the uvea, particularly inferiorly due to the additional influence of gravity
  • ▪
    The stroma of the ciliary body contains the ciliary muscle, or the muscle of accommodation

    • –
      The ciliary muscle is derived from neural crest tissue
    • –
      The ciliary muscle is smooth muscle in mammals and striated in birds and most reptiles
    • –
      The ciliary body vasculature is highly permeable, with fenestrated capillaries, thus making no functional contribution to the blood-aqueous barrier
• •
  The ciliary body epithelium

  • ▪
    The ciliary body epithelium is a two-layered epithelium derived from neuroectoderm of the optic cup

    • –
      The cells of these two mono-layers are oriented apex-to-apex
    • –
      The inner epithelium is non-pigmented except immediately adjacent to the iris epithelium, where it may contain pigment
    • –
      Ciliary epithelium actively secretes aqueous humor against a pressure gradient
    • –
      The ciliary epithelium secretes extra-cellular matrix proteins which assemble to form the zonular ligaments suspending the lens
    • –
      The ciliary epithelium secretes hyaluronic acid which provides substance to the vitreous body
  • ▪
    Inner, non-pigmented ciliary epithelium

    • –
      Junctional complexes in the apico-lateral membranes of the inner, non-pigmented epithelial cells represent the ciliary body's contribution to the functional blood-aqueous barrier. Disruption of this barrier by inflammation and other disease processes results in an increase in the protein content of aqueous humor, clinically detectable as aqueous flare
    • –
      The inner epithelium is continuous with the neuro-sensory retina
    • –
      The basal lamina of the non-pigmented epithelium forms the boundary between the ciliary epithelium and the vitreous body and the posterior chamber

      • ○
        Anatomically as well as functionally, the vitreous body and the posterior chamber both represent modified extracellular spaces and not luminal spaces. This feature is important to our understanding of how these spaces are invaded by blood vessels and spindle cells during disease states
    • –
      The ciliary epithelium secretes hyaluronic acid. The hyaluronic acid is secreted apically and must be transported around the cell toward the vitreous body in extra-cellular ‘channels’ visible on Alcian blue staining
    • –
      The inner, non-pigmented epithelium of the ciliary body is often laden with lympho-plasmacytic inflammatory cells in chronic inflammation and also in lymphoma

      • ○
        This observation leads one to speculate that the non-pigmented epithelium serves a function in immune-regulation
    • –
      The native inner epithelium is vimentin positive and cytokeratin negative, a staining pattern which is unusual among epithelial tissues
  • ▪
    The outer, pigmented epithelium

    • –
      The basal lamina of the pigmented epithelium of the ciliary body lies at the junction with the stroma
    • –
      The outer epithelium of the ciliary body is continuous with the retinal pigment epithelium.

The posterior uvea: the choroid

The choroid (Fig. 9.3 ) is the vascular tunic of the posterior segment.

• •It supplies vascular perfusion for the highly metabolically active and oxygen dependent outer retina via the choriocapillaris
• •The choroid usually contains abundant melanocytes and serves as a pigmented lining of the rigid globe, which reduces internal light reflection and also functions as a ‘sink’ that traps free-radicals.

Figure 9.3.

Normal choroid. (A) Photomicrograph of the normal canine retina and tapetal choroid. There is no pigment in the retinal pigment epithelium. (B) Higher magnification of a perfusion-fixed primate outer retina and choroid. The perfusion fixation makes the choriocapillaris easily appreciated (arrows). Using standard surface fixation this important vascular structure collapses and is hard to detect. (C) Photomicrograph of the canine tapetal retina and choroid showing a thicker tapetum than in (A). (D) The normal feline tapetum is thicker and has a brown tincture. (E) Fibrous tapetum from a horse. (F) Plastic section of a canine tapetum showing the characteristic parallel stacking of the tapetal cells in dogs. A blood vessel (arrow) passes through the tapetum to feed the choriocapillaris.

The suprachoroidal space

The suprachoroidal space is a potential space immediately adjacent to the sclera, which often expands and fills with edema, hemorrhage, or exudates in disease states. It is continuous anteriorly with the supraciliary space and plays an important role in unconventional outflow of aqueous humor.

The choroidal stroma

The choroidal stroma contains many large arteries and veins supplying blood to the choriocapillaris, a capillary bed with a very high rate of perfusion.

The choriocapillaris

• •The choriocapillaris is a highly fenestrated capillary bed supplying nutrition to the outer retina
• •The choriocapillaris is defined internally by Bruch's membrane, which is a multi-layered basement membrane complex formed by the basal laminae of the capillary endothelium and the retinal pigment epithelium, with variable amounts of collagen and elastin fibers.

The tapetum lucidum

• •
  Most of the common domestic mammalian species have a highly reflective tapetum lucidum positioned between the choriocapillaris and the medium-sized vessel layer of the choroidal stroma, superior to the optic nerve head. The peak wavelength of the light reflected by the tapetum is thought to be tailored to that particular species' biological niche

  • ▪
    The cellular tapetum

    • –
      All carnivores have a cellular tapetum made up of regularly arranged cells. Each tapetal cell contains precisely oriented organelles (rodlets) that reflect light in the visible spectrum

      • ○
        The canine tapetum, in common with that of all carnivores except cats, has a highly variable thickness and the reflective rodlets are composed of a zinc-cysteine complex. The canine tapetum can be so thin that it may not be apparent by light microscopy and one must rely on identification of the non-pigmented RPE to determine the location of the superior fundus
      • ○
        The feline tapetum is distinct from that of the dog, in that it is consistently thicker and the reflective rods, which are more precisely oriented, are made up of a riboflavin-zinc complex. This type of tapetum is strongly autofluorescent
  • ▪
    The fibrous tapetum

    • –
      Domestic herbivores generally have a tapetum made up of cell-poor, regularly oriented layers of collagen
• •The overlying retinal pigment epithelium lacks pigment in the area of the tapetum
• •Penetrating vessels can be seen in cross-section to pass from the medium-sized vessel layer through the tapetum at right angles, then terminate in the choriocapillaris.

Comparative Comments.

While in general terms the anatomy of the human uvea conforms to that described for other species, differences exist – some subtle and some profound. Often, when confronted with an eye from a non-human species, an ophthalmic pathologist can find distinctive clues to the identity of that species from the appearance of the iris, ciliary body, or choroid and tapetum lucidum. Although a broad class of retinal diseases in humans is referred to as tapeto-retinal degeneration, the human does not have a reflective, cellular, or fibrous tapetum lucidum positioned between the choriocapillaris and the choroidal stroma. The presence of the tapetum lucidum is always intriguing when seen by pathologists accustomed mainly to human eyes.

Congenital conditions

The morphologic features of the canine blue eye (Fig. 9.4)

Figure 9.4.

Canine blue eye phenotype. (A) Clinical photograph of a Siberian Husky eye with a partially blue iris (heterochromia iridis). (B,C) Low magnification photomicrographs, from the same eye as (A), showing pigmented side, (B), and blue side, (C). (D) Gross photograph of the globe from a blue-eyed Husky illustrates the lack of pigment in both the anterior and posterior uvea. There is still pigment in the epithelium of the iris and ciliary body and, to a lesser extent, the RPE. (E) Photomicrograph of the iris from a canine blue eye stained by immunohistochemistry for glial fibrillary acidic protein (GFAP). The image shows expected positive staining in the nerves, in the dilator muscle and around muscles. There is also a plexus of positive staining at the anterior surface (arrows) that is not seen in similarly stained brown irides. (F) Low magnification photomicrograph showing the non-pigmented and hypoplastic choroid (arrow) in a blue eye.

• •In the absence of pigment within the iris stroma, the iris color will appear blue because of the diffraction of incident light within the iris stroma. The absence of pigment is due to a genetic color diluting effect, e.g. associated with the merle gene in dogs, on melanocytes of the body that are derived from the neural crest, including those of the hair coat and the stromal tissues of the uveal tract. The lack of pigment is not always uniform. For example, in some animals only one eye is blue while the other is brown (heterochromia irides), or in some eyes only a portion of the iris is blue (heterochromia iridis)
• •The iris epithelium and the retinal pigment epithelium have a distinct neuroepithelial embryological origin, and are normally pigmented
• •Iris stroma is devoid of pigment but not usually significantly hypoplastic. In contrast, the choroid of affected eyes is not only devoid of melanin, but variably hypoplastic. Likewise, the tapetum is often hypoplastic or absent
• •The canine blue eye contains no identifiable melanocytes in the iris stroma when stained, by immunohistochemistry, for melanocytic markers. However, premelanosomes have been described in the cytoplasm of cells presumed to be melanocytes when examined with transmission electron microscopy. Feline and human blue irides have stromal melanocytes, but their cytoplasm lacks melanosomes.

Uveal coloboma

See Collie eye anomaly and anomalies associated with merle ocular dysgenesis in Chapter 3.

Iris hypoplasia and aniridia (Fig. 9.5)

Figure 9.5.

Equine iris hypoplasia. (A) Clinical photograph of a horse with iris hypoplasia. Ciliary processes are visible at the margins of the overly wide pupil. (B) Subgross photomicrograph of the eye in (A) showing the undersized irides.

• •
  Iris hypoplasia generally affects only iris stromal tissue and may be localized to specific zones of the iris.

  • ▪
    Blue irides are most often affected, although pigmented irides may also be hypoplastic
  • ▪
    Hypoplastic tissue may appear thin in cross-section, or clinically may appear to bulge anteriorly
  • ▪
    In horses, zones of iris stromal hypoplasia are commonly observed superior to the pupil margin. Clinically these often appear to bulge anteriorly
• •
  Sporadic reports of cases diagnosed clinically as aniridia generally represent examples of severe iris hypoplasia, with rudimentary iris tissue. True aniridia is very rare

  • ▪
    Bilateral aniridia has been reported in horses, and in some breeds may be a familial trait
  • ▪
    Aniridia is a rare, sporadic abnormality in other species, but has been documented in Llanwenog sheep in the UK
  • ▪
    Dermoid, or corneal vascularization, has been reported as a concurrent finding in aniridia, often involving the superior limbus
  • ▪
    Congenital cataract is also a frequent finding
• •
  There are three equine cases of severe iris hypoplasia in the COPLOW collection.

  • ▪
    All three cases in the COPLOW collection also have epithelial thickening at the limbus with hyperkeratosis but not true dermoid
  • ▪
    All three cases also had concurrent cataract
• •Diffuse iris stromal hypoplasia is also observed in Siamese cats with inherited congenital glaucoma (see Ch. 13)
• •Hypoplasia of the iris dilator muscle, clinically appreciated as a miotic pupil, is a characteristic feature of the complex of congenital ocular anomalies seen in Rocky Mountain horses (see Ch. 3).

Persistent pupillary membranes (PPM)

• •
  These strands of uveal tissue represent remnants of the vessels and mesenchyme of the anterior tunica vasculosa lentis, or pupillary membrane, a sheet that normally overlies the anterior surface of the lens during development.

  • ▪
    The tunica vasculosa lentis mostly regresses by the time of birth, or within the first several weeks of life, depending on the species and their degree of ocular maturity at birth
  • ▪
    PPM represent a delay in, or failure of, normal regression of the anterior tunica vasculosa lentis
• •PPMs are a common incidental finding, recognized sporadically in dogs and horses. An inherited predisposition has been reported in several breeds of dog, most notably the Basenji
• • PPM may also occur in association with other lesions, including microphthalmic syndromes, and with local cataract or corneal opacity if they attach to the anterior lens capsule, or corneal endothelium respectively
• •Peter's anomaly, refers to a more severe spectrum of anterior segment malformation characterized by persistent sheets of mesenchyme and corneal and lens opacities (see Ch. 3).

Degenerative, hyperplastic, and age-related conditions

Iris atrophy (Fig. 9.6)

Figure 9.6.

Iris atrophy. Siamese, 13 years old: the tapetal reflex can be seen in the thin temporal iris. It is especially obvious through the many iris holes.

• •
  Iris atrophy is seen as an age-related change in several species

  • ▪
    Progressive thinning of the iris stroma can lead to the appearance of ‘holes’ in the iris that should be distinguished from congenital iris hypoplasia or colobomas
• •Atrophy can also be a feature in chronic glaucoma or after trauma.

Cysts of the irido-ciliary epithelium

• •
  Sporadic iridal cysts (Figs 9.7 , 9.8 )

  • ▪
    Cysts of the posterior iris epithelium may be recognized in any species, and occur commonly in dogs. They may affect any breed, being particularly common in Labrador and Golden retrievers, but are seldom of clinical significance
  • ▪
    The pigmented epithelium of the iris or, less frequently, the inner epithelium of the ciliary body, undergoes spontaneous cystic hyperplasia, in the absence of inflammation or any other apparent predisposing factors

    • –
      Similar cystic changes may affect the iris epithelium associated with the corpora nigra in horses, and if sufficiently large, can impact vision
    • –
      Acquired iris cysts, in cats, are a consistent morphological feature seen in eyes with a history of blunt trauma, or with other morphologic features suggestive of blunt trauma
    • –
      Spontaneous iris cysts are more likely to be bilateral and multiple in cats than in dogs and horses
  • ▪
    Clinical appearance and complications of iris cysts

    • –
      Cysts can break off and float free in the anterior chamber, although in cats they generally remain attached to the iris epithelium. Very rarely, they can move into the vitreous
    • –
      In dogs and horses, these cysts are typically spherical or ovoid and often darkly pigmented although they may vary in their degree of pigmentation. Feline iris cysts tend to be black, or very darkly pigmented, and are often more elongated and ovoid in appearance than canine iris cysts
    • –
      Cysts can masquerade as pigmented masses and careful clinical evaluation is essential to avoid inappropriate removal of the eye. As they are thin-walled, iris cysts can be distinguished from other pigmented masses (neoplasms) by trans-illumination using a bright light source
    • –
      Cysts can make contact with the lens, resulting in focal capsular opacity, and may even initiate posterior synechiae
    • –
      Cysts can adhere to the endothelial surface of the cornea, and if they rupture or collapse, may be a source for endothelial pigmentation or atrophy
    • –
      The presence of multiple uveal cysts in the posterior chamber can lead to collapse of the ciliary cleft and anterior displacement of the iris with closure of the irido-corneal angle, but secondary glaucoma is not common.
• •
  Pars plana cysts in cats and horses (Fig. 9.9 )

  • ▪
    Cystic hyperplasia of the non-pigmented epithelium of the pars plana is a common finding in aged cats
  • ▪
    The cysts are filled with Alcian blue-staining hyaluronic acid, which is digested by treatment with hyaluronidase
  • ▪
    These cysts have no known clinical significance
  • ▪
    Cysts of the pars plana epithelium also occur in aged horses (see Ch. 11)
• •
  Multiple irido-ciliary cysts in Golden Retriever dogs, ‘pigmentary uveitis’ (Figs 9.10 , 9.11 )

  • ▪
    The occurrence of multiple, thin-walled, irido-ciliary cysts is an important cause of glaucoma in Golden Retrievers. Within the COPLOW collection, there are 134 cases, representing 20% of glaucomas diagnosed in Golden Retrievers
  • ▪
    Based entirely on submissions to the COPLOW collection, this condition was most prevalent in the Golden Retriever population in the North-eastern United States in the 1990s, which may reflect the common ancestry of this population
  • ▪
    The condition is seldom diagnosed in Golden Retrievers in Europe, although a very similar condition has been reported in Great Danes. There is one case in a Great Dane in the COPLOW collection, and occasional cases with similar morphology in other breeds have been diagnosed at COPLOW
  • ▪
    There are significant differences between the clinical presenting features and the histopathological features of this disease:

    • –
      Clinically, the disease presents as uveitis with aqueous flare, and proteinaceous and cellular debris and pigment recognized in the anterior chamber. Typically there is also pigment adherent to the lens capsule, often in a radial pattern, and to the posterior cornea, hence the clinical term ‘pigmentary uveitis’. The condition often affects both eyes, although disease involvement is not generally symmetrical
    • –
      Histologically, the main defining characteristic of this disease is the presence of thin-walled epithelial cysts filling the posterior chamber and draped against the lens capsule and anterior face of the vitreous body. Inflammation is variable, and not consistently seen
    • –
      Affected globes are often heavily pigmented and free melanin pigment in the irido-corneal angle might play an important role in the pathogenesis of inflammation or glaucoma. Reduction in aqueous outflow by viscous material liberated from ruptured cysts, or simply anterior displacement of the iris by multiple cysts in the posterior chamber, could also contribute to the development of secondary glaucoma in affected dogs
    • –
      It should be acknowledged that, in a pathology collection, only severely affected globes, often with secondary glaucoma, are available for histopathological evaluation
  • ▪
    Morphologic features of multiple irido-ciliary cysts in Golden Retrievers

    • –
      Thin-walled epithelial cysts, that may be either pigmented or non-pigmented, extending across the posterior chamber

      • ○
        Cyst epithelium is thin, almost squamous in appearance
      • ○
        A PAS stain often reveals a magenta-staining basal lamina along with the epithelial cells
      • ○
        A cell-poor collagenous matrix may also be identified, adjacent to the cyst epithelium or attached to the lens capsule
    • –
      Cyst walls or portions of cyst walls are adherent to the anterior face of the vitreous body or the equatorial lens capsule

      • ○
        When present on the lens capsule, the cyst epithelium often extends anteriorly, towards the anterior pole of the lens. These pigmented thin epithelial fragments are probably what is recognized as pigment adherent to the lens clinically
    • –
      Posterior synechiae or iris bombé are frequently seen in globes removed because of secondary glaucoma
    • –
      Preiridal fibrovascular membranes are commonly encountered, often with concurrent peripheral anterior synechiae
    • –
      Focal retro-corneal membranes are often seen, frequently with pigment entrapment

      • ○
        Fragments of thin-walled cysts are seldom, if ever, recognized in the anterior chamber
    • –
      Intraocular hemorrhage is often seen
    • –
      Free pigment in the irido-corneal angle may play a role in the development of glaucoma, just as it might in glaucoma associated with goniodysgenesis.
• •
  Multiple irido-ciliary cysts are a characteristic finding in Rocky Mountain horses with an inherited complex of congenital ocular anomalies (see Ch. 3)

  • ▪
    The cysts are thin-walled and translucent and are generally present in both eyes of affected horses.

Comparative Comments.

The major congenital and developmental abnormalities of the human uveal tract are colobomas, aniridia, persistent pupillary membrane, persistence of the tunica vasculosa lentis, and iris cysts.

Figure 9.7.

Canine iris or ciliary body cysts. (A) Boston Terrier, 11 years old: the large central cyst is adherent to the corneal endothelium. (B) Labrador Retriever, 7 years old: multiple cysts are present at the pupil margin. Several cysts are filled with blood (arrows). (C) Golden Retriever, 3 years old: both eyes had multiple cysts visible at the pupil margin. The one large translucent cyst is free floating in the anterior chamber. (D) Gross photograph taken with a dissecting microscope showing pigmented iridal cysts on a canine posterior iris.

Figure 9.8.

Feline iris or ciliary body cysts. (A) Siamese, 7 years old: two heavily pigmented cysts originate at the pupil margin. (B) DSH, 11 years old: a faint tapetal reflex can be seen through this large cyst. (C) DSH, 8 years old: large cysts, which transilluminate poorly, were present in both eyes. (D) DSH, 7 years old: a diffuse cortical cataract and large cysts are present. (E,F) Subgross and low magnification photomicrographs showing pigmented epithelial cysts attached to the posterior epithelium of the feline iris (arrows). This is often a feature of the traumatized feline eye.

Figure 9.9.

Pars plana cysts feline and equine. (A) Gross photograph showing cysts on the pars plana of the ciliary body in an aged feline eye (arrow). (B) Photomicrograph showing ciliary epithelial cysts filled with Alcian blue positive material (hyaluronic acid) (Alcian blue PAS). (C) Gross photograph showing a cluster of pars plana cysts (*) in an aged horse.

Figure 9.10.

Golden Retriever thin-walled cysts (pigmentary uveitis), clinical. (A) Golden Retriever, 7 years old: the irides were both hyperpigmented. Focal areas of anterior capsule pigmentation (arrow) are present. Iris cysts could not be visualized on ocular examination. (B) Golden Retriever, 5.5 years old: pigment swirls are present (arrow) primarily at the equatorial lens. (C) Golden Retriever, 11 years old: posterior synechia resulted in an irregular pupil. A large white proteinaceous mass (between arrows) is present in the anterior chamber. (D) Golden Retriever, 10 years old: strands of posterior synechia (arrows) are present. Corneal edema and an anterior chamber proteinaceous mass contributed to the axial opacity.

Figure 9.11.

Golden Retriever thin-walled cysts (pigmentary uveitis), pathology. (A) Gross photograph showing the iris, posterior chamber, and remnants of thin-walled cystic structures stretched between the pars plicatus and the lens equator (white arrow). Posterior synechia and pigmented fragments of cysts adhere to the lens (black arrow). (B) Photomicrograph showing epithelial membranes and cyst walls crossing the posterior chamber and adherent to the anterior vitreous face. (C) Partially pigmented thin epithelial membrane is adherent to the lens capsule. (D) Iris bombe in an affected Golden Retriever. Notice the pigmented epithelial membrane (arrow) broadly adherent to the lens capsule. (E) Higher magnification photomicrograph showing thin epithelial cells and a small amount of blue collagen matrix adherent to the lens capsule (trichrome stain).

Neovascular proliferation and tissue fibrosis in the uvea (Fig. 9.12)

Figure 9.12.

Fibrovascular membrane proliferation. (A) Low magnification photomicrograph of a canine iris showing a preiridal fibrovascular membrane (arrow) and ectropion uveae on the anterior surface. (B) Photomicrograph showing preiridal fibrovascular membrane (arrow) and peripheral anterior synechia in a dog. A circumferentially affected globe would likely have neovascular glaucoma. (C) Gross photograph of a canine globe showing a preiridal fibrovascular membrane (arrowheads), cyclitic membrane (*), and an early fibrovascular membrane extending into the vitreous from the optic nervehead (arrow). (D) Subgross photomicrograph of a dog eye showing an extensive cyclitic membrane (*). (E) Photomicrograph of a dog eye showing a choroidal fibrovascular proliferation (arrow). (F) Siberian Husky, 10 years old: detail of iris architecture is lost. No tapetal reflex can be seen. Posterior synechia (arrow) resulted in a secondary glaucoma.

Neovascular proliferation

The uvea is prone to neovascular proliferation and tissue fibrosis in circumstances which favor local production of cytokines, most prominently vascular endothelial growth factor (VEGF)

• •
  Conditions that are commonly associated with uveal neovascular membranes in domestic animals include:

  • ▪
    Uveitis
  • ▪
    Trauma, including intraocular surgery
  • ▪
    Intraocular neoplasia
  • ▪
    Retinal detachment and associated retinal hypoxia
  • ▪
    Other causes of ocular or retinal hypoxia or ischemia, including glaucoma
• •
  Common sites of uveal neovascular membrane formation are:

  • ▪
    Pre-iridal fibrovascular membrane (PIFVM), which is most commonly recognized on histopathology

    • –
      Since there is no epithelial lining to the anterior iris surface, the new vessels and fibroblasts that constitute the fibrovascular membrane do not have to penetrate an epithelium, as would be required at other sites of fibrovascular proliferation within the eye
    • –
      PIFVM is seldom mentioned as a clinical finding on pathology submission forms

      • ○
        In dogs, however, careful slit-lamp biomicroscopic examination by an experienced observer may be required to identify PIFVM, which is much more difficult to appreciate clinically against the darker background of the typical, brown canine iris
      • ○
        Clinicians may recognize the effects of PIFVM, rather than directly identifying the membrane itself, e.g. by identifying ectropion or entropion uveae, whereby the pupillary zone of the iris is distorted by the contractile effects of a PIFVM
  • ▪
    Posterior iridal fibrovascular membrane
  • ▪
    Cyclitic membrane

    • –
      Fibrovascular tissue penetrates the ciliary epithelium and extends across the anterior vitreous face, incorporating the ciliary processes. Advanced cases can span the globe across the anterior vitreous and extend behind the lens
  • ▪
    Intravitreal membranes, extending from the pars plana into the body of the vitreous. Intravitreal membranes are generally associated with intraocular hemorrhage
  • ▪
    Intravitreal, or epiretinal membranes extending from the optic nerve head into the body of the vitreous and on the inner surface of the retina are infrequently recognized in domestic animals
• •In contrast to the human eye, the eyes of domestic animals seldom develop proliferative membranes directly on the retinal surface, (proliferative vitreoretinopathy or epiretinal membranes)
• •It is appropriate here to re-emphasize that the chambers of the eye, the anterior and posterior chamber and the vitreous body, are not luminal spaces. Rather, they are modified, cell-poor, extracellular spaces. As such, it comes as no surprise that they are easily invaded by fibrovascular membranes.

Fibrovascular proliferation

Fibrovascular proliferation (granulation tissue formation) is almost never seen within the uveal tissue proper.

• •It can therefore be assumed that there is some inhibitory process at work within the uveal tissues, preventing the formation of harmful scar tissue directly within the uveal stroma.

Clinically significant complications of fibrovascular proliferation

• •Intraocular hemorrhage
• •
  Synechiae

  • ▪
    Peripheral anterior synechiae
  • ▪
    Posterior synechiae
• •Traction within the vitreous leading to retinal detachment
• •Glaucoma.

Neoplastic membranes

Neoplastic membranes on the anterior surface of the iris are a prominent feature in metastatic neoplasia. See later in this chapter for further discussion of metastatic neoplasia involving the uvea.

Comparative Comments.

In the human, one of the most important and intensely studied examples of neovascular proliferation is in the wet or exudative type of age-related macular degeneration. These eyes have fibrovascular tissue present between the inner and outer layers of Bruch's membrane, beneath the retinal pigment epithelium or in the subretinal space. This leads to fluid leakage giving rise to serous retinal detachments, and vessel rupture, resulting in subretinal and intraretinal hemorrhages.

Inflammation-uveitis

Clinical and pathologic diagnoses

Distinct and separate criteria are used by the clinician and by the pathologist in the diagnosis of uveitis. Thus, in some cases, it can be difficult to reconcile clinical and pathologic diagnoses.

• •The clinical diagnosis of uveitis relies heavily on the manifestation of aqueous flare, an indication of protein or cells in the aqueous humor. Protein in the aqueous humor is very difficult for the histopathologist to demonstrate
• •The histopathologic diagnosis of uveitis relies on the demonstration of cellular hallmarks of inflammation directly within the uveal stroma. There is no reliable way to make this determination clinically.

Feline lympho-plasmacytic uveitis (L-P uveitis) (Fig. 9.13)

Figure 9.13.

Feline lymphoplasmacytic anterior uveitis. (A) DSH, 6 years old: multiple Busacca nodules (arrow) are present over the entire iris. Toxoplasmosis was the presumed etiology based on serology. (B) Siamese, 6 months old: the iris is severely swollen. A severe aqueous flare and miosis are also present. Bartonella was the presumed etiology based on serology. (C) Gross photograph showing the anterior uvea of a cat with lymphoplasmacytic uveitis. Multiple lymphoid nodules appear as raised tan round foci (arrow). There is also considerable recession of the irido-corneal angle. (D) Gross photograph of an affected cat eye showing a localized flare in the vitreous adjacent to the posterior lens capsule (arrow) typical of the release of lens protein. When the flare is seen, it is not known whether the lens protein contributes to or is the cause of uveitis. (E) Photomicrograph of the iris from an affected cat showing intense inflammatory infiltration with lymphocytes and plasma cells, including the formation of lymphoid follicles (*). (F) Low magnification photomicrograph showing condensed vitreous in the posterior chamber (arrow) of an affected cat. (G) Photomicrograph of the posterior pole of the lens and vitreous showing the typical granular appearance of the released lens protein material, similar to that shown in (D).

There are 558 cases of feline lympho-plasmacytic uveitis in the COPLOW collection, 11% of feline submissions.

• •
  Lympho-plasmacytic uveitis is one of the most common causes of feline glaucoma and, in the COPLOW collection, is second only to diffuse iris melanoma as the most common cause of feline glaucoma resulting in enucleation

  • ▪
    Although L-P uveitis in cats is not always clinically associated with glaucoma, globes with concurrent glaucoma are overwhelmingly more likely to be submitted to COPLOW for histopathologic evaluation
• •
  Although much studied, the etiopathogenesis of L-P uveitis in cats has not yet been elucidated, with many cases being termed idiopathic

  • ▪
    Lympho-plasmacytic inflammation is also commonly seen in traumatized eyes, suggesting that L-P uveitis is a non-specific feline ocular immune response that may be initiated by multiple causes
  • ▪
    Based on serologic studies, Toxoplasmosis and Bartonellosis have been cited as potential etiologic agents
• •
  Morphologic features of L-P uveitis in cats include:

  • ▪
    Lymphocytes and plasma cells in the anterior uvea

    • –
      The ratio of lymphocytes to plasma cells can vary dramatically between cases
    • –
      The absolute numbers of inflammatory cells can also vary dramatically between cases, and is important, neither to the diagnosis of L-P uveitis, nor to the subsequent development of secondary glaucoma
  • ▪
    Formation of lymphoid follicles in the iris stroma or the anterior ciliary body stroma

    • –
      Although not all cases demonstrate lymphoid follicles, these are a feature that is not commonly seen in response to chronic uveitis in other species, except horses
  • ▪
    Lymphocytic cells within the non-pigmented epithelium of the ciliary body
  • ▪
    Many cases have lens luxation or subluxation

    • –
      This morphologic feature needs to be assessed at the time of globe trimming
  • ▪
    Many cases demonstrate vitreous liquefaction

    • –
      This morphologic feature also needs to be assessed at the time of globe trimming
    • –
      Whereas the bulk of the vitreous body may be liquid, the anterior vitreous face often appears abnormally dense or condensed
  • ▪
    Changes in the anterior vitreous:

    • –
      it is important to use an Alcian blue-PAS stain to evaluate the anterior vitreous
    • –
      The anterior face of the vitreous often contains an excess of spindle cells and collagen
    • –
      The anterior vitreous is often displaced into the posterior chamber or through the pupil, into the anterior chamber
    • –
      Granular hypereosinophilic protein may be observed in the anterior vitreous, adjacent to the posterior lens capsule

      • ○
        Although it is not always possible to demonstrate a break in the thin, posterior lens capsule, this abnormality of the anterior vitreous that is suggestive of lens protein leakage is seen relatively frequently. In these cases, the inflammation observed may represent a lens-induced uveitis
• •
  Mechanisms of secondary glaucoma in L-P uveitis

  • ▪
    Many assume that secondary glaucoma is related to obliteration or occlusion of the drainage angle structures by inflammation or attendant pre-iridal fibrovascular membranes, however, lens luxation and/or anterior vitreous prolapse may also be implicated in some cases.

Equine recurrent uveitis (ERU), periodic ophthalmia, moon blindness (Figs 9.14, 9.15)

Figure 9.14.

Equine recurrent uveitis, clinical. (A) American Saddlebred Horse, 7 years old: severe miosis and posterior synechia resulted in only two small areas of visible pupil (arrows). (B) Appaloosa, 10 years old: chronic uveitis resulted in an irregular pupil margin and a yellow discoloration of the vitreous. (C) Thoroughbred, 6 years old: in addition to the aqueous flare, hypopyon is present inferiorly. (D) Thoroughbred, 10 years old: aqueous flare, dyscoria, and an anterior cortical cataract (arrow) are present in this case. (E) Thoroughbred, 6 years old: peripapillary chorioretinopathy, called a ‘butterfly’ lesion, and anterior uveitis are present in this eye. (F) American Standardbred, 4 years old: hyalitis, optic neuritis, and radiating retinal detachment (arrow), termed a sunburst detachment, are present.

Figure 9.15.

Equine recurrent uveitis, pathology. (A) Gross photograph of equine eye showing an inflammatory membrane tightly adherent to the inner aspect of the ciliary body (arrows) in equine recurrent uveitis (ERU). (B) Photomicrograph of an affected horse showing a lymphoplasmacytic infiltrate in the ciliary body stroma including a lymphoid follicle (arrow), a feature highly suggestive of ERU. (C) A photomicrograph of the pars plicata of the ciliary body of an affected horse showing a membrane of cell-poor amyloid-like protein (arrows). (D) Photomicrograph of the ciliary body epithelium showing numerous inflammatory cells within the epithelium and hypereosinophilic linear inclusions in the cytoplasm of the affected cells (small arrows). The lower inset shows these bodies at a higher magnification. (E) Photomicrograph showing green birefringence of a Congo red-stained section of the ciliary body of an affected horse. The birefringent membrane is the same one illustrated in (C).

There are 78 cases of equine recurrent uveitis in the COPLOW collection, 20 of them in Appaloosa horses.

• •ERU is the most common cause of cataract, glaucoma, phthisis bulbi and blindness in horses
• •There is a breed predilection for the Appaloosa
• •It is important to be aware that not all cases of uveitis in horses are attributable to ERU
• •The clinical syndrome is characterized by recurrent bouts of inflammatory disease leading to progressive ocular degeneration. In some horses the disease has an insidious onset, with minimal clinical signs noted until significant secondary complications, such as cataract, glaucoma and/or phthisis bulbi become apparent
• •
  The etiopathogenesis of ERU has not been definitively established and many causes have been postulated. However, current evidence implicates Leptospiral ocular infection and auto-immunity as the important factors in the pathogenesis ERU

  • ▪
    Evidence to support the role of Leptospirosis in the pathogenesis of ERU includes:

    • –
      Inoculation of susceptible ponies with Leptospira interrogans serovar pomona causes a syndrome of recurrent uveitis that is clinically and histopathologically indistinguishable from ERU
    • –
      Some affected horses have elevated antibody titers and the titers are even higher in the aqueous
    • –
      Leptospira serovars have been detected by culture and/or PCR in vitreous and aqueous, and even fixed ocular tissues of affected horses. However, this has been a very inconsistent finding in ERU cases in North America compared with ERU cases from continental Europe
    • –
      While Leptospirosis may induce uveitis in horses, the recurrent nature of inflammation in ERU most-likely reflects the role of auto-immunity in its pathogenesis
  • ▪
    Evidence that supports a role for auto-immunity in the pathogenesis of ERU includes:

    • –
      During the active phase of the disease, there are circulating or local antibodies to various ocular proteins
    • –
      Leptospira organisms are not consistently detected in ocular fluids and tissues of all affected horses
    • –
      Immunopathologic studies support the ‘auto-aggressive’ nature of the disease, demonstrating a preponderance of CD4+ T-cells and increased transcription of IL-2 and IFN-γ with low IL-4, that are characteristic of a Th1-like inflammatory response
    • –
      A role for retinal auto-antigens, including inter-photoreceptor binding protein, cellular retinaldehyde binding protein, recoverin and retinal-S antigen (arrestin), has been demonstrated in experimental models and spontaneous ERU
    • –
      Immunogenetic investigations have suggested an association between ERU susceptibility and certain equine lymphocyte antigen (ELA) haplotypes
    • –
      Some affected horses develop a subclinical lymphocytic inflammation in the pineal gland which shares many antigens with the retina
• •
  Distinctive morphologic features of ERU include:

  • ▪
    Lympho-plasmacytic uveitis, with lymphoid follicle formation in some cases. Equine recurrent uveitis and feline L-P uveitis are the two diseases in which this feature is prominent. Lymphoid follicles are otherwise a rare finding in the uveal tract
  • ▪
    Lymphocytes and/ or plasma cells within the non-pigmented ciliary epithelium
  • ▪
    Hypereosinophilic linear inclusions in the cytoplasm of non-pigmented ciliary body epithelial cells

    • –
      Masson's trichrome stain facilitates the identification of these bright red-staining, intra-cytoplasmic inclusions
    • –
      By electron microscopy these inclusions represent crystalline arrays of protein. At the margins of the inclusions, fragments of a double membrane are seen suggesting that the inclusions develop within mitochondria, breaking through the membrane
  • ▪
    Deposition of a cell-poor hyaline protein on the inner surface of the non-pigmented ciliary body epithelium

    • –
      Stains positive with Congo red stain, a feature of amyloid
    • –
      Shows green birefringence when viewed with intense polarized light, which is also a feature of amyloid
    • –
      Stains blue with Masson's trichrome, which is typical of collagen
    • –
      Filaments have ultrastructural characteristics suggestive of collagen
• •
  Other morphologic features of ERU, which are common findings but not necessarily specific, include:

  • ▪
    Cataract
  • ▪
    Retrocorneal membranes and corneal wrinkling
  • ▪
    Anterior and/or posterior synechiae
  • ▪
    Fibrovascular membranes
  • ▪
    Retinal detachment and/or retinal degeneration
  • ▪
    Optic nerve inflammation, degeneration and gliosis
• •
  It appears that significant posterior uveitis, characterized by pronounced chorioretinal disease and vitreous opacification, is less frequently observed in the USA than in Europe

  • ▪
    This may reflect differences in the ability to establish persistent intraocular infections between the predominant Leptospira isolates from ocular fluids of horses with ERU in Europe (L. kirschneri serovar Grippotyphosa, strain Duyster) and North America (L. interrogans serovar Pomona).

Canine uveodermatologic syndrome, Vogt–Koyanagi–Harada-like syndrome (VKH) (Figure 9.16, Figure 9.17, Figure 9.18)

Figure 9.16.

Canine uveodermatologic syndrome (VKH-like), clinical. (A) Japanese Akita, 10 months old: periocular, nasal and labial depigmentation is present. (B) The left eye of the dog in (A) showing corneal edema and vascularization. A poorly dilated pupil is also present. (C) Samoyed, 14 months old: severe erosion and depigmentation are seen at the labium and nasal planum. (D) The left eye of the dog in (C) showing severe corneal edema and chemosis. (E) Japanese Akita, 3 years old: limbal edema and a swollen iris are present. (F) Siberian Husky, 18 months old: dyscoria and engorged iris vessels are present. Pigment is visible on the anterior lens (arrow).

Figure 9.17.

Canine uveodermatologic syndrome (VKH-like), fundus. (A) Japanese Akita, 6.5 years old: optic neuritis is present in this blind dog. The arrow points to one of the many areas of abnormal pigmentation in the tapetal retina. (B) Japanese Akita, 3 years old: the optic disc is poorly visualized. The arrow points to the edge of a large bullous detachment. (C) Samoyed, 8 months old: retinal vessels are dilated. The optic disc is swollen and the entire retina is edematous and elevated. (D) Japanese Akita, 7 years old: the arrows delineate a large bullous retinal detachment. (E) Samoyed, 2 years old: a swollen optic disc, dilated retinal vessels, and tapetal pigment changes are present. (F) Samoyed, 5 years old: the same eye as in (E), 3 years later, showing the loss of the tapetum and pigment in the retinal pigmented epithelium and choroid.

Figure 9.18.

Canine uveodermatologic syndrome (VKH), pathology. (A,B) Gross photographs showing both globes from two dogs with canine uveodermatologic syndrome, illustrating the diffuse thickening of the affected uvea and the bilateral symmetry that is characteristic of the disease. The globes in (B) are fixed in Bouin's solution, which accounts for the yellow color. (C) Subgross photomicrograph of the globe from an affected dog showing diffuse uveal thickening due to a histiocytic inflammatory cell infiltrate. Retinal detachment is seen but the retina, vitreous and aqueous are relatively quiet. (D) Photomicrograph of the choroid from an affected dog showing a histiocyte-rich infiltrate, causing thickening of the choroid behind the tapetum.

There are 83 cases of uveodermatologic syndrome in the COPLOW collection, 23 of which are in Akitas.

• •This canine uveo-dermatologic syndrome is considered a model for human Vogt–Koyanagi–Harada syndrome
• •The Akita breed is predisposed to uveodermatologic syndrome
• •
  The human disease generally affects dark-skinned people between 20 and 50 years old and is most common in Japan. The bilateral uveitis is accompanied by pigment loss in the skin and/or hair. The human disease is strongly related to certain HLA tissue types

  • ▪
    Increased frequency of certain DLA class alleles has been identified in Akitas in the USA, and these alleles carry a higher relative risk for uveodermatologic syndrome
• •Canine uveodermatologic syndrome and human VKH are both thought to be an autoimmune disease that targets melanin or a component protein expressed in melanocytes. Tyrosinase, or tyrosinase-related proteins are considered to represent strong candidates as the target antigen. Peptides from tyrosinase related protein-1 have been used to induce experimental uveodermatologic syndrome in Akitas
• •
  Clinically the syndrome is characterized by uveitis that is generally bilaterally symmetrical and unilateral disease is rare. Retinal detachment and glaucoma are seen in many cases

  • ▪
    A case report describing a dog with unilateral disease provides an interesting insight into the pathogenesis. This dog had asymmetric uveal pigment dilution (heterochromia irides), the blue eye being spared the panuveitis recognized in the brown eye
• •Poliosis, vitiligo and alopecia are frequently recognized, with depigmentation that may be localized to the facial region, particularly to the nasal planum and lips, or may be generalized
• •
  Morphologic features of canine uveodermatologic syndrome include:

  • ▪
    The hallmark feature of uveodermatologic syndrome is granulomatous uveitis

    • –
      Uveal inflammation is always histiocyte-rich

      • ○
        Some dogs have marked uveal thickening because of solid sheets of histiocytic inflammation, whereas others have no thickening and a very bland histiocytic infiltrate
      • ○
        Histiocytes are peppered with melanin granules
      • ○
        Inflammation can be more severe in any part of the uvea but the choroid is always affected
      • ○
        The distribution of the inflammation is highly variable but, if both eyes are available for examination, the symmetry in distribution between eyes is striking
    • –
      There is a mismatch between the degree of granulomatous inflammation observed in the uvea, and the relatively ‘quiet’ appearance of the vitreous, aqueous, retina, and cornea
    • –
      Granulomatous inflammation centered on pigmented cells is a defining feature of canine uveodermatologic syndrome

      • ○
        Clusters of histiocytes within the choroid and subtending the pigmented retinal pigment epithelium (RPE) in a manner reminiscent of Dalen-Fuchs nodules. In humans, these collections of epithelioid cells between the RPE and Bruch's membrane are associated with certain forms of granulomatous uveitis, including VKH and sympathetic ophthalmia
    • –
      In skin biopsies from affected dogs with de-pigmentation there will be histiocytic inflammation, with melanophage cells subtending the surface epithelium
    • –
      Inflammation of the meninges is common in the human disease but appears to be rare in dogs.

Canine asymmetric uveitis (Fig. 9.19)

Figure 9.19.

Canine asymmetric uveitis. (A) Poodle, 14 years old: chronic uveitis resulted in severe corneal edema and superficial corneal vascularization in the right eye. (B) This is the left eye, previously normal, of the dog in (A), 3 months later. The detail of the anterior segment is difficult to view due to the severe flare and fibrin. Hypopyon is present at the arrow. (C,D) Gross photographs of globes from two different dogs with asymmetric uveitis showing an inflammatory membrane lining the anterior uvea (arrows) and considerable exudates in the aqueous and vitreous and around the detached retina. (E) Photomicrograph of the choroid of an affected dog showing a macrophage-rich membrane carpeting the inner choroid and subretinal space (arrows). (F) Photomicrograph of the iris from an affected dog showing a macrophage-rich membrane carpeting the surface of the iris front and back (arrows).

• •
  There are 79 cases of asymmetric uveitis in the COPLOW collection, 17 of which are in Poodles, however the records seldom report which Poodle type. Although this diagnosis is made fairly frequently in the COPLOW submissions, the condition has not been reported in the veterinary literature.

  • ▪
    There are 52 females and 24 males among the cases with this diagnosis
• •
  If the histopathological features of asymmetric uveitis are identified in an enucleated globe, then the remaining eye should be considered at risk of developing uveitis with similar morphologic features. Early and aggressive anti-inflammatory therapy may prevent severe ocular disease in the second eye

  • ▪
    There are 23 cases in the COPLOW collection with confirmed disease in the second eye including 10 cases in which the second eye was submitted and had similar pathologic features to the original eye
  • ▪
    The time between enucleation of the first eye and the clinical onset of disease in the second eye ranged from almost immediately to 4 years
• •
  The diagnosis of asymmetric uveitis is dependent on recognition of a characteristic pattern of granulomatous uveitis with the following morphologic features:

  • ▪
    Sheets of pyogranulomatous inflammatory cell infiltrate, forming a blanket-like covering on the inner surface of any part of the uveal tract or the inner retina. Rarely, this ‘blanket’ of inflammation extends across the posterior cornea

    • –
      Histiocytic cells tend to line up perpendicular to the uveal surface
  • ▪
    Inflammation within the retina and segmental retinal necrosis
• •The same morphologic features will be seen in the second eye if it is submitted for evaluation, concurrently or subsequently
• •Aside from the characteristic features which define asymmetric uveitis, in most instances the first affected globe shows other features suggesting a penetrating injury such as lens capsule rupture, scleral defect, sepsis in the globe or a foreign body. However, evidence of a penetrating injury is not always identified and a history of trauma is seldom reported by the submitting clinician. Careful scrutiny of serial sections may be required to identify such evidence of penetrating injury or episcleral inflammation
• •Severe uveitis that develops in some dogs with diabetic cataract, with lens protein-associated, macrophage-rich endophthalmitis, presents a histological appearance that is very similar to asymmetric uveitis.

Lens-induced uveitis, phacolytic uveitis (Fig. 9.20)

Figure 9.20.

Phacolytic uveitis (lens-induced uveitis). (A) Siberian Husky, 1 year old: the iris is severely inflamed with intrastromal hemorrhage. (B) Bichon Frise, 3 years old: chronic inflammation of the iris resulted in the increased iris pigment. (C) Cocker Spaniel, 1.5 years old: the iris is swollen, and ectropion uvea is present. (D) Golden Retriever, 1 year old: the iris is heavily pigmented and ectropion uvea is present 360° at the pupil. (E) Gross photograph of a dog eye with hypermature cataract and lens-induced uveitis phacolytic uveitis). (F) Subgross photomicrograph of a dog eye with lens-induced uveitis, and the wrinkled remnants of the lens capsule in hypermature cataract. (G,H) Gross photographs of dog eyes with hypermature cataract, chronic uveitis, posterior synechia and retinal detachment with secondary glaucoma.

There are 50 cases of lens-induced uveitis in the COPLOW collection. Because this phenomenon is commonly seen as part of a complex, multifaceted disease process, it is likely that the condition is significantly under-represented in our collection.

• •Lens-induced uveitis almost invariably accompanies mature, intumescent or hypermature cataract. Induction of an inflammatory response within the uvea is thought to occur secondary to the leakage of lens proteins through an intact lens capsule, as part of a degenerative process that also results in lens shrinkage and capsule wrinkling
• •
  Morphologic features of lens-induced uveitis include:

  • ▪
    Mild to moderate lympho-plasmacytic infiltrate in the anterior uveal stroma. This is a non-specific change and the diagnosis of lens-induced uveitis should only be made if the lens pathology is appropriate and there are no other changes identified that are consistent with a different pathogenesis
  • ▪
    Globes removed and submitted for histopathology often have glaucoma associated with posterior synechiae, iris bombé, or pre-iridal fibrovascular membranes with extensive peripheral anterior synechiae
• •
  Phacolytic uveitis in the special case of rapidly progressing, intumescent diabetic cataract and lens capsule rupture (Figs 9.21 , 9.22 )

  • ▪
    In the COPLOW collection, there are 15 cases of macrophage-rich endophthalmitis in diabetic dogs with intumescent cataract and lens capsule rupture
  • ▪
    Diabetic cataract often develops very rapidly in dogs, with large amounts of modified lens proteins being released into the aqueous, either passing through an intact lens capsule or after lens capsule rupture
  • ▪
    The morphology of macrophage-rich endophthalmitis in diabetic dogs differs from most inflammatory diseases which occur secondary to traumatic lens capsule rupture (see Ch. 5) in that the macrophage reaction is widely distributed in the eye and not centered on the lens. There are similarities, already mentioned, to asymmetric uveitis
  • ▪
    The morphologic features of uveitis associated with diabetic cataract include:

    • –
      Protein exudation in the anterior chamber and vitreous
    • –
      A histiocyte-rich cellular infiltrate in the uvea
    • –
      Histiocytic inflammatory cells on the inner retinal surface and extending into the retina.

Figure 9.21.

Phacolytic uveitis in diabetic cataract, clinical. (A) Black and Tan Coonhound, 9 years old: the intumescent lens can be seen. Iritis and limbal edema are also present. (B) Poodle, 10 years old: iritis with ectropion uvea is present. The pupil is severely miotic. (C) Miniature Schnauzer, 6.5 years old: severe corneal edema and lipid aqueous flare prevent visualization of the large fibrin clot in the anterior chamber and the poorly dilated pupil. (D) Miniature Schnauzer, 5 years old: the ventral endothelium has multiple keratic precipitates (arrow).

Figure 9.22.

Endophthalmitis secondary to diabetic cataract, pathology. (A,B) Gross photographs of dog eyes with intense uveitis and endophthalmitis secondary to diabetic cataract. (C,D) Subgross photomicrographs of two dogs with diabetic cataract and resultant macrophage-rich uveitis. (E) Photomicrograph of an affected dog eye showing hypereosinophilic lens protein free in the anterior chamber. (F) Photomicrograph of the iris from an affected dog showing a membrane of phagocytic inflammatory cells carpeting the posterior surface of the iris, similar to that seen in asymmetric uveitis. (G) Photomicrograph of the exudates in the posterior vitreous showing many macrophage cells adjacent to and within the retina.

Intraocular xanthogranuloma (Fig. 9.23)

Figure 9.23.

Canine intraocular solid xanthogranuloma. (A) Gross photograph of a canine globe totally effaced by a bright yellow xanthogranuloma (B) Photomicrograph of xanthogranuloma showing sheets of foamy macrophage cells and crystals (arrows) (C,D) Photomicrographs similar to (B) except using polarized light to highlight the birefringent crystals. The light in (D) is manipulated for color effect.

• •This rare complication of hyperlipidemia may masquerade as intraocular neoplasia
• •There are five cases in the COPLOW archive, all in diabetic and hyperlipidemic Miniature Schnauzers
• •All five dogs had a history, or other evidence, of chronic uveitis and secondary glaucoma
• •
  Morphologic features of intraocular xanthogranuloma include:

  • ▪
    On gross inspection, distorted, firm globes, that appear to be essentially filled with a solid, heterogeneous, light tan mass
  • ▪
    The intraocular structures are effaced by a mixture of lipid-laden macrophages (‘foam cells’), and Alcian blue-positive, birefringent crystals
  • ▪
    Atherosclerosis of episcleral blood vessels.

Uveal involvement in systemic infections and parasitic diseases

General comments:

• •Many systemic infectious diseases, including viral, protozoal, bacterial, mycotic and parasitic infections, affecting domestic species are commonly associated with ocular disease in veterinary patients
• •Clinical signs referable to uveitis may be the initial reason for presentation in many of these disorders
• •In addition to the systemic infectious causes of uveitis discussed in this chapter, Bartonellosis, Brucellosis, Borreliosis, Ehrlichiosis, Leishmaniasis, Leptospirosis, Mycobacterial infection and Rocky Mountain spotted fever, are just some of the many potential causes of infectious uveitis
• •The relative importance of many systemic infectious diseases, with respect to their prevalence and clinical significance, varies widely depending on species and geographic location

We have chosen here to discuss only conditions which have been diagnosed in the COPLOW collection. We recognize that in many cases, specific infectious causes may be under-represented, because the changes seen in infectious uveitis can be non-specific making it impossible to make a specific diagnosis based on histopathological findings alone.

Feline infectious peritonitis (FIP)

There are 41 cases of FIP (Fig. 9.24 ) in the COPLOW collection.

• •Although young cats are most commonly affected, the collection includes six cases in cats over 5 years old
• •The prevalence is greatest in cats housed in multi-cat environments.

Figure 9.24.

Feline infectious peritonitis (FIP). (A) DSH, 5 months old: corneal vascularization and edema are present. Multiple keratic precipitates can be seen by retroillumination. (B) DSH, 4 months old: a large fibrinous clot (arrow) fills the anterior chamber. (C) Siamese, 4 months old: the retinal vessels are dilated. Retinal hemorrhage and intraretinal white exudate are present. (D) Siamese, 5 months old: the retinal vessels are dilated, and the entire retina is edematous. Multiple areas of intraretinal exudate are present at the arrows. (E,F) Gross photographs of cat globes with feline infectious peritonitis (FIP) showing the aqueous and vitreous with a translucent and semi-solid appearance, because the high protein content of the exudates is fixed semisolid with formalin. (G,H) Photomicrographs showing the mixed nature of the cellular infiltration in FIP.

FIP is caused by a virulent biotype of feline coronavirus and is a relatively common disease that is presently incurable, and generally considered to be fatal.

Feline coronavirus infection may be limited to the gastrointestinal tract but some virulent strains acquire the ability to replicate within macrophages. In cats that do not mount an appropriate, strong, cell-mediated immune response to the virus, disseminated infection can develop, leading to FIP.

Three main variants of FIP are recognized, on the basis of their clinical and pathological presentation:

• 1.
  Effusive, ‘wet’ form

  • ▪
    Characterized at necropsy by clear, protein rich, viscous fluid exudates in one or more body cavities and fibrinous exudates adherent to the serosal surfaces
  • ▪
    Ocular involvement is less common in the purely effusive form of the disease
• 2.
  Non-effusive, ‘dry’ form

  • ▪
    Characterized by pyogranulomatous inflammation in the parenchyma of the kidney, liver, lung or any of several other organs
  • ▪
    Ocular and/or neurological involvement is often a feature of this form of the disease
• 3.
  Neuro-ocular FIP

  • ▪
    This can be seen in the absence of other systemic manifestations, or in combination with the dry form of FIP, but seldom accompanies the wet form of the disease
  • ▪
    Neurological involvement can occur in combination with ocular disease, or either manifestation can occur in isolation.

Morphologic features of ocular involvement with FIP:

• •Although textbook descriptions suggest that histopathology is the best way to definitively diagnose this condition, as a pathologist it is always a challenge to make this diagnosis because the features of FIP are diverse and highly variable
• •The COPLOW experience indicates that histopathological diagnosis of ocular FIP presents a challenge. Key to establishing a diagnosis is the recognition of the interplay of multiple different morphologic patterns, each of which adds an increment of credence to the diagnosis of ocular FIP. However, the pathologist's best effort often leads to only a tentative diagnosis of FIP.
• •
  Gross lesions

  • ▪
    One of the most important lesions indicative of FIP is the observation of highly proteinaceous, cell-poor exudates in the aqueous and vitreous body. The protein is fixed by formalin, or other fixative used, and is seen as a semisolid, translucent exudate filling the sectioned globe
• •
  Microscopic lesions

  • ▪
    Mixed inflammatory cellular infiltrate in the uvea, retina, optic nerve and/or meninges

    • –
      The predominant cell type is variable
    • –
      Finding localized areas of plasma cell-rich infiltrate is helpful
    • –
      Finding areas of suppurative inflammation is not particularly helpful in establishing a diagnosis, but relatively common in this disease
    • –
      Finding areas of granulomatous inflammation is helpful, although not as consistent a feature as in generalized FIP in other, non-ocular sites

      • ○
        If granulomatous inflammation is found, it is helpful if macrophage cells with mildly dysplastic nuclear features are identified
      • ○
        Identifying vasculitis is an important diagnostic feature but not absolutely necessary
    • –
      FIP is an ultimately fatal, infectious disease, so caution should be exercised in making an equivocal diagnosis without careful consideration of the clinical findings, supporting clinical pathology results and, where possible, documentation of coronavirus antigens within tissues by immunohistochemistry or PCR. However, detection of coronavirus antigens has proven to be an unreliable test in the experience of COPLOW.

Toxoplasmosis

Although toxoplasmosis is frequently cited and well documented as a cause of uveitis in cats, there are few cases of toxoplasmosis associated with uveitis in any species in the COPLOW collection.

• •Most commonly reported in cats, which are the organism's host species, ocular toxoplasmosis may occur in association with other systemic signs of disease
• •
  A number of studies also support a causal role for toxoplasmosis in some cases of uveitis in cats that show no other signs of systemic infection

  • ▪
    However, the role and importance of Toxoplasma gondii infection in the pathogenesis of feline lympho-plasmacytic uveitis in otherwise healthy cats remains controversial
• •
  Carnivorous or omnivorous species become infected by ingesting bradyzoites (tissue cysts containing hundreds of dormant organisms) in the tissues of other animals

  • ▪
    Alternatively, animals may be infected by ingestion of sporozoites in foodstuffs or water contaminated by cat feces containing oocysts
  • ▪
    Once ingested, these infective stages transform into tachyzoites that are disseminated in a wide range of body tissues, including the CNS, muscles, viscera, and eyes, before becoming dormant bradyzoites
• •Toxoplasma gondii is reported to elicit a granulomatous and/or lympho-plasmacytic inflammatory response
• •In reported cases of naturally occurring cases and in experimentally induced disease, toxoplasmosis lesions are most frequently identified in the anterior uvea, choroid and retina, and less frequently in the optic nerve.

Mycotic uveitis

• •
  Comparative aspects:

  • ▪
    Although all of these diseases occur in humans, with the exception of histoplasmosis, ocular involvement is rare
  • ▪
    The ‘presumed ocular histoplasmosis syndrome’ in humans occurs most frequently in the Ohio River valley where histoplasmosis is common. However, the diagnosis is made based on clinical appearance, rather than by demonstrating the presence of the organism within ocular tissues
  • ▪
    In humans, disseminated mycoses with ocular involvement may be encountered in immunocompromised individuals
• •
  Blastomycosis, Blastomyces dermatitidis (Figs 9.25 , 9.26 )

  • ▪
    There are 140 cases of Blastomycosis in dogs and eight cases in cats in the COPLOW collection

    • –
      Blastomycosis is the most commonly reported disseminated mycotic infection in dogs
  • ▪
    Blastomycosis is a systemic mycotic infection, most common in the Mississippi River valley. The disease is also endemic in the Ohio and Missouri River valleys and the mid-Atlantic and southern states of the United States
  • ▪
    The disease occurs in very localized ‘hot beds’ of infection related to ‘point source’ exposure. Many cases live in close proximity to water courses
  • ▪
    The disease is considerably more prevalent in dogs than it is in humans and more prevalent in humans than it is in cats

    • –
      In humans, the disease seldom affects ocular structures other than the eyelid but can be associated with endophthalmitis
  • ▪
    This dimorphic fungus is found in acidic soils, particularly those with decaying wood, and is infective only by inhalation of spores from infectious soil or by direct implantation into a penetrating wound. While transmission to humans from dogs is theoretically possible by this latter route, the zoonotic potential of blastomycosis is very low
  • ▪
    The disease in dogs:

    • –
      Blastomycosis is typically a disease of young adult dogs who spend a lot of time outdoors, particularly hunting or working breeds
    • –
      The primary site of infection is the lung, which is the most commonly affected, and earliest, organ to develop lesions
    • –
      Other organs commonly affected include the eye, skin, lymph nodes, and bone. Any other tissue may be involved occasionally
  • ▪
    Morphologic features of ocular involvement in blastomycosis include:

    • –
      Most commonly, a chorioretinitis is identified, that may be nodular or multifocal. Posterior segment involvement is most common, although the location of lesions in the globe or orbit is highly variable
    • –
      The inflammation is pyogranulomatous in all cases, although ‘classical’ nodular granulomas are not typical
    • –
      The diagnosis is dependent on finding the yeast form of the organism in histological sections or cytological preparations
    • –
      Morphologic features of the Blastomyces dermatitidis organism in tissue include:

      • ○
        Exquisitely round, typically 10–15 µm diameter yeast form
      • ○
        One micron refractile cell wall
      • ○
        Broad-based, budding forms
      • ○
        Live organisms have an amphophilic central body and dead organisms have only an empty cell wall
      • ○
        Free organisms are often surrounded by Splendore–Hoeppli reaction
      • ○
        Histopathological findings in eyes with endophthalmitis related to blastomycosis do not appear to be significantly affected by anti-fungal treatment compared to untreated eyes, e.g. in their degree and type of inflammation and identification of budding yeast forms
  • ▪
    Blastomycosis in cats:

    • –
      The disease in cats differs only minimally from that in dogs, although it is much rarer and feline blastomycosis is more likely to involve the central nervous system than canine blastomycosis
• •
  Cryptococcosis, Cryptococcus neoformans (Figs 9.27 , 9.28 )

  • ▪
    There are 12 cases in dogs and 23 cases in cats in the COPLOW collection

    • –
      Cryptococcosis is considered to be the most common disseminated mycotic infection in cats
  • ▪
    Cryptococcosis affects many species as a systemic yeast infection, but only dogs and cats with ocular involvement are represented in the COPLOW collection
  • ▪
    Immunosuppression plays a role in the establishment of disseminated infection, especially in humans
  • ▪
    Cats are more commonly affected than dogs but the clinical syndromes are similar in these species
  • ▪
    Cryptococcosis has a worldwide distribution and is acquired by the inhalation of spores from infectious soil. The infectious stage is often a contaminant in pigeon droppings
  • ▪
    The nasal cavity is the earliest and most likely site to become infected
  • ▪
    The tissues of the upper respiratory tract, CNS, lymph nodes, skin, and eyes are most commonly affected by cryptococcosis
  • ▪
    The definitive diagnosis of ocular cryptococcosis is dependent on identification of the organism in affected tissues or cytological preparations. Serological testing to detect cryptococcal antigen is also useful, particularly in monitoring response to therapy
  • ▪
    Morphologic features of ocular cryptococcosis include:

    • –
      Most commonly, a multifocal, granulomatous chorioretinitis, although the infection can involve any part of the eye or orbit
    • –
      Pyogranulomatous inflammation is the most frequently observed type of inflammatory reaction. However, in some cases there is minimal cellular infiltrate

      • ○
        The degree of inflammation appears to be inversely related to the thickness of the mucoid capsule on the infecting organism
      • ○
        In cases with minimal or no inflammatory cellular component, the organisms are often found in blood vessel lumina
    • –
      Morphologic features of the Cryptococcus neoformans organism in tissue include:

      • ○
        The yeast cell body ranges from 5 to 8 µm in diameter, and stains poorly with H&E, which reveals no visible internal structure
      • ○
        The central yeast is surrounded by a thick polysaccharide capsule which does not stain with H&E. The capsule is between 3 and 10 µm thick
      • ○
        The central yeast organism stains magenta with PAS, and the mucoid capsule stains blue with Alcian blue, or bright red with mucicarmine stain
      • ○
        In contrast to blastomycosis, budding forms will not be found in Cryptococcosis
      • ○
        Very rarely, short pseudohyphae are seen.
• •
  Histoplasmosis, Histoplasma capsulatum (Fig. 9.29 )

  • ▪
    There are two cases in dogs and 16 cases in cats in the COPLOW collection. However, the organism is often hard to find in cats, and there may be many more cases that go undiagnosed
  • ▪
    Histoplasmosis is a systemic disease, occurring worldwide, that affects many species, but only dogs and cats with ocular involvement are represented in the COPLOW collection
  • ▪
    The dimorphic fungus, Histoplasma capsulatum exists as infective hardy spores in the soil, particularly in soil rich in bird or bat droppings
  • ▪
    In the USA, the disease is most common in the Mississippi and Ohio River valleys
  • ▪
    The primary site of infection is in the lungs, following the inhalation of infective spores
  • ▪
    Disseminated histoplasmosis commonly affects the lungs, intestine, lymph nodes, skeleton, skin and eyes, although involvement of any part of the body may be seen
  • ▪
    Morphologic features of ocular histoplasmosis include:

    • –
      Pyogranulomatous uveitis, although there is a highly variable distribution of inflammation in the globe or in orbital tissues
    • –
      In cats there is often a thick spindle cell layer internal to the choroid as well as proliferation of the RPE. This is similar in many ways to the reaction seen in humans in the ‘Presumed ocular histoplasmosis syndrome’ (Fig. 9.30 )
    • –
      The diagnosis depends on demonstrating the organism within tissues, which requires PAS or a silver stain for fungus

      • ○
        The organism is always intracellular, within macrophage cells, and may be numerous or there may be only a few organisms. Furthermore there may be cases in which the organisms are too few to find, or nonexistent in the eye, as is often the case in humans
    • –
      Morphologic features of Histoplasma capsulatum in tissue include:

      • ○
        The organism is small, only 3–5 µm in diameter, and is always located within macrophage cells
      • ○
        The organism has a ‘target’ appearance with H&E, but stains uniformly black with silver stains
      • ○
        Budding is not seen
• •
  Coccidioidomycosis, Coccidioides immitis (Fig. 9.31 )

  • ▪
    There are 21 cases in dogs and seven cases in cats in the COPLOW collection
  • ▪
    Coccidioidomycosis is a systemic disease endemic in the southwestern desert regions of the USA, as well as other low-lying deserts in Central and South America. The disease is acquired by inhalation of spores from the desert soil and animals that have prolonged outdoor exposure show enhanced risk of infection
  • ▪
    Immunosuppressed animals are at particular risk of disseminated infection but the disease is also seen in otherwise healthy individuals
  • ▪
    Many species are susceptible to infection but only dogs and cats with ocular involvement are represented in the COPLOW collection
  • ▪
    The disease commonly affects the lungs, bones, and eyes, however any tissue may be affected
  • ▪
    Morphologic features of ocular involvement include:

    • –
      Pyogranulomatous inflammation in the tissues affected. In the eye, the pattern of disease is variable, although chorioretinitis is a common feature. Ocular involvement is often unilateral
    • –
      Coccidioidomycosis is diagnosed by demonstration of the organism in tissue sections or cytological preparations
    • –
      The organism exists in small numbers in tissues, but it is large and easily recognized
    • –
      The organism is more numerous, therefore more easily identified, in cat eyes than in dog eyes
    • –
      Morphologic features of Coccidioides immitis in tissues include:

      • ○
        The spores from the soil, upon establishing infection in the tissues, transform into large spherules ranging from 20 to 85 µm in diameter
      • ○
        The spherules consist of a thick, refractile, outer cell wall, containing small, 2–4 µm subunits called endospores
      • ○
        Budding is not seen, but the mature spherule bursts releasing numerous endospores
• •
  Canine systemic (disseminated) aspergillosis (Fig. 9.32 )

  • ▪
    In cases where the eye is submitted to COPLOW, ocular disease often precedes signs of systemic illness
  • ▪
    There are 21 cases of canine systemic aspergillosis in the COPLOW collection and of these, nine are in German Shepherd dogs, a breed that appears to be predisposed to opportunistic fungal infections
  • ▪
    Affected dogs have widely disseminated infection and the diagnosis carries a poor prognosis
  • ▪
    Widespread vasculitis is a prominent feature of the systemic disease
  • ▪
    Immune deficiency, or aberrant immune response, is thought to be important in the pathogenesis of systemic aspergillosis. The disseminated disease in humans almost exclusively affects immunocompromised individuals and patients with a history of intravenous drug abuse
  • ▪
    Morphologic features of ocular disease in canine systemic aspergillosis include:

    • –
      Panophthalmitis, often with the most severe exudate being identified, grossly and histologically in the vitreous body
    • –
      Fungal organisms are most likely to be found in the vitreous body adjacent to the inner retina
    • –
      Organisms are sometimes found within the lens capsule and capsular rupture may be a feature

      • ○
        The hyphae may be found directly within the lens capsule, which should therefore be carefully scrutinized, because the organisms are very apparent in this location, even with H&E stain.
    • –
      Morphologic features of Aspergillus sp. in tissue include:

      • ○
        Filamentous fungi that have septate hyphae, with parallel cell walls and dichotomous branching
      • ○
        Silver stains are usually required to facilitate recognition of the hyphae
• •
  Aspergillosis in birds

  • ▪
    Although aspergillosis is a common cause of death in birds, there are only two cases of endophthalmitis and two cases of keratitis associated with aspergillus infection in avian eyes in the COPLOW collection.

Figure 9.25.

Blastomycosis, anterior segment, clinical. (A) Boxer, 3 years old: the pupil is dilated and a mild aqueous flare is present. Chemosis and a hyperemic conjunctiva are seen in this acute case. (B) Miniature Schnauzer, 5 years old: the iris is swollen and the pupil is miotic. Corneal edema and vascularization obscures the view of the leukocoria caused by the posterior segment granuloma. (C) Foxhound, 3 years old: severe corneal edema and limbal deep vessels hinder visualization of the anterior segment exudate. (D) Cocker Spaniel, 2 years old: the leukocoria is caused by the extensive subretinal exudate. Poorly-defined retinal vessels can be seen at the arrow.

Figure 9.26.

Blastomycosis, fundus and pathology. (A) Mixed Breed, 3.5 years old: the entire retina was edematous with dilated vessels. A large subretinal granuloma is present. (B) Mixed Breed, 2.5 years old: only one subretinal granuloma was found in the inferior nasal fundus. (C) DLH, 11 years old: the entire inferior retina is elevated by subretinal exudate. Retinal hemorrhage is present and all retinal vessels are tortuous and poorly defined. (D) DSH, 5 years old: the optic disc (black arrow) is poorly defined due to the total bullous detachment. Subretinal exudate is present at the white arrow. (E–G) Three gross photographs of sectioned canine globes with pyogranulomatous inflammation caused by Blastomyces dermatiditis. (H) Photomicrograph showing a multinucleated macrophage cell with a PAS-positive Blastomyces organism in the cytoplasm. (I) Photomicrograph of a Blastomyces organism with ‘broad-based budding’. (J) Photomicrograph of Blastomyces yeast organism surrounded by spikes of protein, the Splendore–Hoeppli phenomenon.

Figure 9.27.

Cryptococcosis, anterior segment, clinical. (A) German Shepherd, 6 years old: white nodules of inflammatory infiltrate obscure the entire iris surface. (B) Mixed Breed, 3 years old: mild anterior uveitis with aqueous flare was present. The leukocoria is due to the totally detached retina and subretinal exudate. (C) DSH, 7 years old: aqueous flare and hyalitis were present. A white fibrinous clot adheres to the endothelium at the arrow. (D) DSH, 11 years old: the white fibrinous clot is present on the anterior lens (arrow). Many black inflammatory nodules are present in the iris.

Figure 9.28.

Cryptococcosis, fundus and pathology. (A) Cocker Spaniel, 6 years old: severe subretinal white exudate is present. (B) German Shepherd, 2.5 years old: the multiple dark lesions represent deep retinal exudate. Areas of peripapillary retinal edema are also present (arrow). (C) DSH, 5 years old: retinal and subretinal exudate is present as multiple foci of pigment. (D) DSH, 5 years old: multiple grey subretinal granulomas are present. (E–G) Gross photographs showing pyogranulomatous inflammatory nodules in the anterior uvea (E) and posterior segment (F,G). (H–J) Low magnification photomicrographs showing an intense chorioretinitis in cryptococcosis (H), numerous organisms in blood vessels with almost no inflammation (I), and a few organisms in the choriocapillaris (J). (K) High magnification of cryptococcal organisms showing the large non-staining mucoid capsule and the poorly stained cell walls of the organisms in the center (H&E). (L) Organisms stained with Alcian blue PAS. The mucoid capsule stains with Alcian blue and the cell walls of the organism stain with PAS. (M) PAS stain showing a pseudohyphal form of Cryptococcus.

Figure 9.29.

Histoplasmosis, fundus and pathology. (A) German Shepherd, 3 years old: the tapetal retina showing multiple areas of pigment proliferation surrounded by retinal edema. (B) DSH, 5 years old: The non-tapetal retina is totally detached and in folds (white arrow). In addition to the many foci of intraretinal exudate, a large subretinal granuloma is present (black arrow). (C) Persian, 6 years old: large and small areas of abnormal deep pigmentation are present. (D) DSH, 8 years old: a pink-colored subretinal exudate detached the retina superiorly and inferiorly. (E–G) Gross photographs showing pyogranulomatous chorioretinitis in cats with histoplasmosis (E,F) and anterior uveitis in an affected dog (G). (H) Photomicrograph showing numerous macrophage cells with cytoplasm rich in organisms. (I) Photomicrograph showing macrophage cells laden with PAS-positive organisms. (J) Photomicrograph showing macrophage cells containing silver-stained Histoplasma capsulatum organisms.

Figure 9.30.

Histoplasmosis, feline, features of ‘presumed histoplasmosis’ (A) Photomicrograph of a feline eye with Histoplasmosis showing retinal detachment (*) and marked thickening of the inner choroid (arrow) with a combination of spindle cell proliferation and mixed inflammation. (B) Photomicrograph from the same cat as (A), showing proliferation of the RPE which is stained by immunohistochemistry for cytokeratin (arrows). (C) High magnification photomicrograph from the same cat as (A), showing macrophage cells in the inner choroid with Histoplasma organisms in the cytoplasm (arrow). (D) Histoplasmosis organisms stained with silver stain from the same field as (C). (E) Domestic shorthaired, 2 years old: leukocoria is due to total retinal detachment and subretinal granulomas. All serology and histopathology of the globes yielded no etiology. Aspirate of the submandibular lymph node identified Histoplasma capsulatum. (F) Domestic shorthaired, 5 years old: bilateral anterior uveitis and chorioretinitis were present. Fungal serology was negative. Histopathology identified Histoplasma capsulatum.

Figure 9.31.

Coccidioidomycosis, fundus and pathology. (A) German Shepherd, 2 years old: a large subretinal granuloma has elevated the retina. (B) Vizsla, 3 years old: generalized chorioretinitis is present. Subretinal granulomas can be seen at the arrows. (C–E) Gross photographs of feline eyes with chorioretinitis (C,D) and a canine eye (E) with episcleral pyogranulomatous inflammation caused by Coccidioides immitis. The inflammatory focus in the dog eye is primarily scleral and episcleral. (F) Photomicrograph of coccidioidal endosporulating spherule (H&E). (G) Photomicrograph of spherules with developing endospores (PAS). (H) Ruptured spherule releasing endospores (Alcian blue PAS).

Figure 9.32.

Canine systemic aspergillosis. (A–C) Gross photographs of three dog eyes showing suppurative endophthalmitis with the primary exudates in the vitreous adjacent to the retina, a feature commonly seen in systemic aspergillosis when it affects the eye. (D) Photomicrograph showing Aspergillus hyphae (arrow) within the lens capsule. (E) Photomicrograph showing fungal hyphae extending from the retinal inner limiting membrane into the vitreous body. (F) Aspergillus hyphae are surrounded by Splendore–Hoeppli (arrow) protein deposition.

Canine ocular protothecosis (Prototheca zopfii or, less often, Prototheca wickerhamii) (Fig. 9.33)

Figure 9.33.

Protothecosis, clinical and pathology. (A) Labrador Retriever, 10 years old: anterior uveitis is present. The deep red tapetal reflex is due to posterior segment hemorrhage. A granuloma is seen at the arrow. (B) The left eye of the dog in (A) showing retinal edema and intraretinal hemorrhage (arrows). The large white mass represents a subretinal granuloma. (C–E) Gross photos of dog eyes affected with protothecosis. Retinal detachment and moderate exudates characterize the disease. (F) Photomicrograph showing subretinal macrophage-rich exudates. Each macrophage cell contains numerous algal organisms (H&E). (G) Photomicrograph of a subretinal exudative process showing numerous PAS+ protothecal organisms. (H) Higher magnification photograph of a touch preparation showing several organisms and the characteristic internal segmentation (Giemsa stain).

There are six cases in the COPLOW collection, all in dogs.

• •Disseminated protothecosis occurs in dogs and is extremely rare in other species
• •The organism is classified as an saprophytic, achlorophyllous alga
• •The organism is common in contaminated water but infection is rare
• •Infection occurs worldwide but the South-eastern United States has a relatively high incidence
• •It is postulated that systemic disease results from ingestion of the organism and invasion of the intestinal mucosa, whereas local infection occurs by contamination of skin wounds
• •
  Clinical syndrome in dogs with systemic disease:

  • ▪
    Clinical signs depend on the tissues affected, but chronic gastro-intestinal signs are often a feature
  • ▪
    Ocular involvement is common in systemic disease and is usually bilateral
  • ▪
    Response to treatment has been discouraging in affected dogs, and the diagnosis of disseminated protothecosis carries a poor prognosis in this species
• •
  Morphologic features of ocular protothecosis

  • ▪
    Retinal separation, often with complete, ‘morning glory’ retinal detachment
  • ▪
    The subretinal space, vitreous, and aqueous contain a dry, granulomatous exudate but not the dense, protein-rich exudate that may be seen with many other infectious causes of endophthalmitis
  • ▪
    Granulomatous inflammation carpeting the outer retina and the inner choroid
  • ▪
    Large numbers of organisms are seen in macrophage cells and free within the tissue
  • ▪
    Morphologic features of Prototheca sp. in tissues

    • –
      One to 10 µm, round to ovoid organisms are surrounded by a thick, refractile cell wall which stains poorly or slightly amphophilic with H&E
    • –
      A few cells undergo endosporulation and may have two or many daughter cells within the cell wall
    • –
      The organisms stain intensely positive with PAS stain.

Canine ocular larva migrans with Toxocara canis (Fig. 9.34)

Figure 9.34.

Toxocara canis ocular larva migrans. (A) Gross photograph of the retinal and pars plana surfaces of the eye from a young dog showing several local granuloma deposits (arrows). (B) Gross photograph of a Bouin's-fixed dog eye showing a migrating larval parasite (arrow). (C) Photomicrograph of three sections of the same larval nematode depicted in (B). (D) Lower magnification of the retina and choroid from an affected young dog showing a mixed inflammation and segmental retinal necrosis (arrow).

There are five cases of ocular larva migrans in the COPLOW collection, all in dogs.

• • Toxocara canis was suspected to be the parasite responsible in all cases
• •In most cases, larva migrans in dogs affects young, working dogs, presumably because of a large parasite burden
• •
  Morphologic features of canine ocular larva migrans include:

  • ▪
    Mild exudates in the vitreous
  • ▪
    Perivascular lymphocytic inflammatory infiltrate in the retina
  • ▪
    Localized granulomatous inflammation

    • –
      It is important to search for the localized granulomas under a dissecting microscope and specifically section through the granulomatous lesions
    • –
      Granulomatous lesions track in and out of the uvea, retina and vitreous
    • –
      Eosinophils are rarely seen in the cases from the COPLOW collection
    • –
      Larval parasites may or may not be found within the granulomata and they may also be found in tissues away from these lesions, particularly in the retina
    • –
      Morphologic features of Toxocara canis larvae in tissue include prominent lateral alae and excretory columns.

Comparative Comments.

As in other species, uveitis in humans is an important and complex group of diseases. A major focus of the histopathologic study of specimens with uveitis is the determination of the cause. Uveitis may result from non-infectious stimuli, such as surgical or non-surgical trauma, and endogenous agents, including tissue necrosis and reactions to allergens. Other non-infectious causes include inflammation associated with systemic diseases and predisposing genetic factors, such as HLA antigens and allergic predispositions. Important categories of non-infectious uveitis in humans include sarcoidosis, Behçet's disease, Vogt–Koyanagi–Harada syndrome, and phacoantigenic uveitis. A fascinating and important disease in this category that occurs only in man is sympathetic ophthalmia. This is a diffuse granulomatous inflammation of the uvea, occurring in the uninvolved eye following injury to the contralateral eye. The onset is usually a few days or weeks after a perforating injury to the exciting eye, or originally damaged eye, but there are well-documented cases of the onset being many years after the initial injury.

In infectious uveitis with a bacterial etiology, there are a number of Gram-positive organisms that have a propensity to invade the choroid from the bloodstream. Granulomatous uveitis is seen with tuberculosis, leprosy, syphilis, Pneumocystis carinii choroidopathy, nocardiosis, and Lyme disease. Major viral causes of uveitis in humans include herpes simplex and herpes zoster viruses, Epstein–Barr virus infection, cytomegalovirus infection, and congenital rubella syndrome. Major fungal causes of uveitis include Candida albicans infection, histoplasmosis and presumed ocular histoplasmosis, cryptococcal infection and Aspergillus infection. Causes of parasitic uveitis in humans include toxoplasmosis, toxocariasis, and onchocerciasis.

Canine ocular melanosis (Fig. 9.35)

Figure 9.35.

Ocular melanosis. (A) Cairn Terrier, 8 years old: the irides are extremely darkly pigmented. Focal subconjunctival pigment is present in the superior sclera. (B) Cairn Terrier, 12.5 years old: the same dog as in (A), 4.5 years later, showing increased subconjunctival pigment and pigment on the anterior lens capsule (arrow). (C) Labrador Retriever, 7 years old: iris detail was lost due to the heavy pigmentation. (D) Boxer, 12 years old: pigment infiltration totally masks iris vasculature. Increased pigment is also present at the pupil margin. (E) Gross photograph of a Cairn Terrier eye affected with ocular melanosis (pigmentary glaucoma). (F) Subgross photomicrograph of a Cairn Terrier globe with glaucoma associated with ocular melanosis. The whole uvea is hyperpigmented, but the iris base and a focus in the pars plana show dramatic nodular expansion. (G) Low magnification photomicrograph showing a heavily pigmented affected iris filled with bland round pigment-rich cells. (H) Low magnification showing a heavily pigmented choroid and optic nerve head in an affected dog.

There are 208 cases of ocular melanosis in dogs in the COPLOW collection:

• •50 in Cairn terriers
• •22 in Boxer dogs
• •31 in Labrador Retrievers.

Ocular melanosis in Cairn Terriers (‘pigmentary glaucoma’)

• •The Cairn Terrier breed is prone to excessive pigmentation of the uvea, with complications which impact on ocular function
• •An autosomal dominant mode of inheritance has been proposed for ocular melanosis in Cairn Terriers
• • Age of onset and rate of progression are variable
• •The disease, in Cairn Terriers is usually bilateral but often not symmetrical
• •
  Clinical features of melanosis in Cairn Terriers include:

  • ▪
    An early recognizable feature is that the iris of affected dogs is very dark brown or black and has a prominent, circumferential ridge at the iris root
  • ▪
    Pigmented particles may be seen free-floating within the aqueous humor, deposited on the anterior lens capsule, or coating the endothelial surface of the cornea and opening to the drainage angle inferiorly
  • ▪
    Dark pigment patches become evident in the anterior sclera and episclera
  • ▪
    With progression, chronic glaucoma ensues, leading to blindness
  • ▪
    In some cases, progressive pigmentation in the posterior segment may be seen, obscuring the tapetum
• •
  Morphologic features of melanosis in Cairn Terriers

  • ▪
    Diffuse over-pigmentation of the uvea

    • –
      An increase in the size of pigmented cells and an increase in the number of pigmented cells
    • –
      Electron microscopy and immunohistochemistry can help to distinguish if the pigmented cells are melanocytes or melanophage cells

      • ○
        Two distinct cell types can be identified within this population of large pigmented cells
      • ○
        The predominant cell type appears to be melanocytes, with different stages of melanosome development visible on electron microscopy. These cells are variably immuno-labelled using markers associated with melanocytes that include HMB45, MITF and vimentin, but not S-100 or Melan-A
      • ○
        A subpopulation of cells have the appearance of melanophages, with melanosomes contained within lysosomal membranes on electron microscopy. Some of these cells are positively immunolabelled by CD-18, indicating that they are indeed melanophages
  • ▪
    Disruption of the normal uveal contour because of excessive pigmentation and excessive accumulation of pigmented cells

    • –
      This disruption is most prominent at the iris base, anterior ciliary body and limbal sclera
  • ▪
    Infiltration of pigmented cells in the limbal sclera and episclera is often quite pronounced, and contributes to a clinical impression of neoplasia
  • ▪
    Acquired staphyloma is seen occasionally
  • ▪
    Some affected eyes also have lympho-plasmacytic uveitis and/or PIFVM
  • ▪
    Melanocytoma or malignant uveal melanoma occasionally occurs in affected eyes
  • ▪
    Distinguishing melanosis from melanocytoma

    • –
      Many pathologists consider ocular melanosis to be a diffuse variant of melanocytoma
    • –
      At COPLOW, the distinct diagnosis of melanocytoma, rather than melanosis, is based on the finding of a regional mass, or a mass which is populated by a mixture of heavily pigmented round cells and heavily pigmented spindle cells. This combination is not seen in melanosis
• •Removal of the eye is generally carried out for the management of glaucoma or to rule out neoplasia.

Canine ocular melanosis in breeds other than Cairn Terriers

• •
  All of the clinical and morphologic features are the same as described for the Cairn Terrier, except that:

  • ▪
    When ocular melanosis occurs in other breeds, it is usually unilateral
  • ▪
    Based on limited electron microscopic studies, melanophages may be the predominant cell type in other breeds.

Comparative Comments.

Ocular melanocytosis occurs in humans, generally as a unilateral diffuse uveal nevus, causing heterochromia of the iris and a darkened choroid, associated with gray patches on the sclera and episclera. If the eyelid and brow are involved, the condition is known as oculodermal melanocytosis. This condition carries a risk of melanoma development in Caucasians.

UVEAL NEOPLASIA

Uveal neoplasia is an important differential consideration in animals that present clinically with intraocular masses, uveitis, intraocular hemorrhage, glaucoma or retinal detachment.

Melanocytic neoplasia

• •
  Melanocytoma in dogs (benign)

  • ▪
    This is a common intraocular neoplasm in dogs.

    • –
      There are 1090 uveal melanocytomas in the COPLOW collection
    • –
      Of these neoplasms:

      • ○
        94% are in the anterior uvea (Fig. 9.36 )
      • ○
        6% are in the choroid (Fig. 9.37 )
  • ▪
    The signalment of affected dogs may be summarized as follows:

    • –
      The average age of affected dogs is 9.7 years

      • ○
        There is a spike in incidence in dogs under 2 years, but otherwise uveal melanocytoma is a disease of older dogs
    • –
      Affected dogs by gender (where known)

      • ○
        Males: 169
      • ○
        Neutered males: 302
      • ○
        Females: 105
      • ○
        Spayed females: 454
    • –
      No specific breeds are over-represented
  • ▪
    Frequently, melanocytoma occurs within heavily pigmented globes or those with melanosis
  • ▪
    Regardless of the extent of invasion, adequate removal by local resection, enucleation or exenteration, is generally curative

    • –
      There are rare but notable exceptions to this generally benign biologic behavior.

      • ○
        In the COPLOW collection, there are three documented cases in which melanocytoma recurred in the orbit as malignant melanoma
    • –
      Photocoagulation of presumed iris melanocytoma in dogs is increasingly carried out by veterinary ophthalmologists, using diode laser. Although uveal melanocytic neoplasia is generally benign in this species and this form of treatment is considered relatively non-invasive, its application in the absence of a definitive, histopathological diagnosis remains somewhat controversial. As malignant melanoma may arise in eyes with melanocytoma (see below), diligent follow-up and monitoring for signs of progression is warranted following laser therapy
  • ▪
    Morphologic features of canine uveal melanocytoma) include (Fig. 9.38 ):

    • –
      Melanocytoma is usually made up of heavily pigmented large round cells and heavily pigmented spindle cells in variable proportions
    • –
      As the tumor takes on a more and more malignant cellular profile, more spindle-shaped, less pigmented cells begin to predominate over a smaller proportion of heavily pigmented round cells
    • –
      The mitotic index is a valuable means of distinguishing between melanocytoma and malignant melanoma

      • ○
        More than four mitotic figures per 10 high power fields is indicative of malignant melanoma (see below) but is not necessarily predictive of malignant behavior
• •
  Malignant ocular melanoma in dogs

  • ▪
    This is less common than benign uveal melanocytoma in dogs.

    • –
      There are 334 cases of malignant ocular melanoma in the COPLOW (Figs 9.39 , 9.40 )

      • ○
        323 are in the anterior uvea
      • ○
        11 are in the choroid
  • ▪
    The signalment of affected dogs may be summarized as follows:

    • –
      The average age of affected dogs is 10.3 years

      • ○
        In contrast to melanocytoma, there is no spike in incidence in the 0 to 2 year age group
    • –
      Affected dogs by gender (where known)

      • ○
        Males: 37
      • ○
        Neutered males: 109
      • ○
        Females: 21
      • ○
        Spayed females: 142
  • ▪
    Frequently, malignant melanoma occurs in eyes with melanocytoma
  • ▪
    Even though malignant ocular melanoma is characterized by histopathological features of malignancy, few metastasize and the prognosis is therefore only slightly guarded
  • ▪
    Morphologic features of malignant uveal melanoma include (Fig. 9.41 ):

    • –
      Malignant melanoma is usually less pigmented than melanocytoma, or is amelanotic
    • –
      Anaplastic nuclear features including anisokaryosis, karyomegaly, folded nuclei, and large nucleoli are characteristic
    • –
      A mitotic index greater than four mitotic figures per 10 high power fields is indicative of malignant melanoma
• •
  Feline diffuse iris melanoma (FDIM) (Figs 9.42 , 9.43 )

  • ▪
    FDIM is a common clinical presentation and pathologic diagnosis in cats

    • –
      There are 1358 cases of diffuse iris melanoma in the COPLOW collection
    • –
      Diffuse iris melanoma accounts for 26% of total feline submissions and 50% of feline neoplasms submitted to COPLOW
  • ▪
    The signalment of affected cats may be summarized as follows:

    • –
      The average age of affected cats is 9.4 years old
    • –
      Affected cats by gender

      • ○
        Males: 55
      • ○
        Neutered males: 643
      • ○
        Females: 65
      • ○
        Spayed females: 541
  • ▪
    Clinical histories indicate that FDIM begins as focal or multifocal areas of iridal pigmentation that are gradually progressive (Fig. 9.44 )

    • –
      In the earliest stage, the pigmentation is strictly confined to the iridal surface. Lesions sampled at this stage are diagnosed as iris melanosis
    • –
      The extent of the pigmented lesions increases either by enlargement of individual spots, or by increase in the number of pigmented spots
    • –
      The disease is designated as early FDIM when the pigment cells extend into the iridal stroma but the extent of involvement is still entirely within the iris
  • ▪
    The progression of disease is highly variable

    • –
      Cases have been documented where the disease has slowly progressed over a 10-year period with little or no apparent effect on the health of the eye, or where FDIM has gradually led to glaucoma
    • –
      Other cases progress rapidly, developing glaucoma and metastases over a short timescale (Fig. 9.45 )
    • –
      At this time, there is no good way to predict the likely progression of disease in individual cats
  • ▪
    This unpredictable progression makes it hard to offer advice on when to enucleate:

    • –
      Some clinicians will remove a globe when they document any evidence of continued growth and progression of pigmented lesions, while others will wait until glaucoma develops
    • –
      Cats with early FDIM at the time of enucleation, that generally have not yet developed glaucoma, survive at the same rate as unaffected cats
    • –
      It is very difficult to accurately estimate the rate of metastatic disease in affected cats. Obtaining documented evidence of metastatic disease may be confounded by long periods of latency in many cases

      • ○
        Most cats with documented metastatic disease had advanced disease, i.e., Extension of the neoplasm beyond the iris and/or neoplastic cells within the scleral venous plexus, at the time of enucleation
    • –
      Metastasis occurs more often to the abdominal cavity/abdominal organs than to the lungs
    • –
      Recurrence in the orbit may also occur
  • ▪
    FDIM demonstrates a tremendous degree of variation in cellular morphology. Within this spectrum of disease, a number of histopathological variants are recognized (Fig. 9.46 ):

    • –
      Round cell or polygonal cell

      • ○
        Most common
    • –
      Spindle cell
    • –
      Balloon cell

      • ○
        Large melanocytes with vacuolated cytoplasm and round, central nuclei
    • –
      Anaplastic variants
    • –
      Giant cells
  • ▪
    Amelanotic variants are often clinically mistaken for inflammatory disease
  • ▪
    Not all cases are strictly diffuse in the iris. Variations in tumor distribution occur where the neoplasm exists as solid localized masses or other cases which are primarily in the ciliary body or even the choroid
  • ▪
    Although uveal melanomas have been experimentally induced in cats by feline sarcoma virus infection, there is no compelling evidence to support an important role for retrovirus infection in the spontaneous development of feline anterior uveal melanoma
• •
  Feline atypical melanoma (Fig. 9.47 )

  • ▪
    This is an uncommon variant of uveal melanoma in cats:

    • –
      There are only 23 cases in the COPLOW collection, representing only 1% of feline neoplasms in the collection
  • ▪
    These are multifocal masses composed entirely of very heavily pigmented round cells, with bland small round nuclei only visible on bleached sections

    • –
      The tumors are distributed throughout the uvea and may involve the iris but, in contrast to FDIM, they are not centered on the iris
    • –
      A characteristic feature, seen in most cases, is the appearance of aggregates of tumor cells on the retinal pigment epithelium, filling the sub-retinal space and extending into the retina
  • ▪
    Despite the bland cellular features, several of these neoplasms have metastasized
• •
  Equine anterior uveal melanocytic neoplasms

  • ▪
    There are 17 cases of equine intraocular melanocytic neoplasia in the COPLOW collection
  • ▪
    Although dermal melanocytic neoplasia is common in horses, equine ocular melanocytic neoplasms are rare, with few reports in the veterinary literature
  • ▪
    Reported cases have generally shown benign histological characteristics.

Comparative Comments.

Uveal malignant melanoma is the most common primary intraocular tumor in adult humans, with an incidence in the United States of approximately six cases per million. These occur predominantly in the choroid (85%) with about 10% in the ciliary body and 5% in the iris.

Except in the iris, uveal malignant melanoma is a highly aggressive tumor, and about half of patients with this type die with metastatic disease within 10–15 years of diagnosis.

In 1931, Colonel George R. Callender at the Armed Forces Institute of Pathology classified these tumors into six types, based on the morphology of the tumor cells. A modified Callender classification continues to be used for the cytologic classification of these tumors.

• •The major categories are spindle cell nevus; spindle cell melanoma; epithelioid melanoma; and mixed-cell type (mixture of spindle and epithelioid cells). This classification has proved less useful in tumors in other species.

Figure 9.36.

Canine anterior uveal melanocytoma. (A) Golden Retriever, 9.5 years old: the pigmented tumor appears to have originated from the ciliary body and extends anteriorly and posteriorly (arrow) to detach the retina. (B) Labrador Retriever, 10 years old: the entire iris has a blotchy pigmentation. An elevated pigmented mass (arrows) resulted in a dyscoria. (C) Mixed Breed, 9 years old: a rise in IOP and corneal edema followed the progression of this diffuse iris tumor. (D) Mixed Breed, 7 years old: this large tumor has resulted in a severe dyscoria, filled the anterior chamber inferiorly, and caused severe corneal edema. (E–G) Gross photographs of dog eyes with prominent melanocytoma within the globe and extending through the sclera at the limbus (G). (H–J) Subgross photomicrographs showing the distribution and staining pattern of anterior uveal melanocytoma. (H) Extensive tumor necrosis and a limbal scleral defect, a common feature of anterior uveal melanocytoma in dogs. These globes can perforate at the limbus, discharging semi-liquid black material.

Figure 9.37.

Canine choroidal melanocytoma. (A) Australian Shepherd, 7.5 years old: retinal edema and elevation surround the rapidly progressing tumor. (B) Chihuahua, 3 years old: an elevated pigmented mass is present in this albinoid fundus. (C) Shetland Sheepdog, 7 years old: the edge of the mass (arrows) is difficult to delineate from the normal choroidal pigment. (D) Golden Retriever, 8 years old: the elevated pigmented mass extends into the nerve fiber layer, represented by pigment feathering on the optic nerve and the temporal peripapillary retina (arrow). (E–G) Gross photographs showing choroidal melanocytoma with or without invasion beyond the sclera. (H–J) Subgross photomicrographs showing choroidal melanocytomas in dogs.

Figure 9.38.

Canine uveal melanocytoma, microscopic. (A) Photomicrograph showing distortion of the papillary margin of the iris in a dog with iridal melanocytoma. (B,C) Photomicrographs showing a combination of heavily pigmented round cells and heavily pigmented spindle cells. This combination of cell types is typical of uveal melanocytoma in dogs. (D) H&E-stained 1-micron section showing the cellular features of the pigmented round cells and the pigmented spindle cells, which characterize uveal melanocytoma.

Figure 9.39.

Canine uveal malignant melanoma, clinical. (A) German Shepherd Dog, 1 year old: the pigmented mass to the left progressed posteriorly to detach the retina. (B) Miniature Schnauzer, 8 years old: the entire iris was diffusely infiltrated, resulting in total loss of the fine iris detail. (C) Mixed Breed, 10 years old: diffuse iris pigmentation, especially obvious at the pupil margin, also resulted in dyscoria. (D) Mixed Breed, 11 years old: extensive intraocular involvement led to glaucoma and severe exposure keratitis of the cornea.

Figure 9.40.

Canine uveal malignant melanoma, pathology. (A) A montage of eight gross photographs of canine globes that contain uveal malignant melanoma. Note the variation in the extent of pigment in the tumors. (B) A montage of four subgross photomicrographs showing canine globes with anterior or posterior uveal malignant melanomas.

Figure 9.41.

Canine uveal malignant melanoma, microscopic. (A,B) Photomicrographs of sections from two dogs with uveal malignant melanoma showing characteristic features of malignancy, including mitotic figures and atypical chromatin distribution.

Figure 9.42.

Feline diffuse iris melanoma (FDIM), clinical. (A) DSH, 9 years old: multiple foci of abnormal pigment are present. Mild elevation of the iris was noted nasally. (B) DSH, 12.5 years old: this is the same cat as in (A), 3.5 years later. Increased pigment plus elevation of the iris due to the infiltration are present. (C) DSH, 12 years old: diffuse pigmentation is present throughout the iris. (D) DSH, 15 years old: this iris is diffusely heavily pigmented. (E) Maine Coon Cat, 13 years old: the iris is diffusely pigmented with focal areas of increased pigment. Dyscoria is present and the mottled tapetal reflex represents pigment (arrow) on the anterior surface of the lens. (F) DSH, 16 years old: the heavily pigmented and infiltrated iris has resulted in a secondary glaucoma. Pigment is present on the anterior lens surface (arrow).

Figure 9.43.

Feline diffuse iris melanoma (FDIM), pathology. (A–F) Gross photographs of feline globes with variable degrees of involvement with feline diffuse iris melanoma (FDIM). Greater involvement increases the risk of metastatic disease. (E) The globe from a blue-eyed Siamese cat with an amelanotic tumor, which would be expected. (F) A globe with an atypical distribution. (G–I) Subgross photomicrographs showing FDIM to variable degrees. The globe in (H) has atypical distribution, because the tumor is not diffuse.

Figure 9.44.

Feline iris melanosis and early FDIM. (A–C) Gross photographs showing the early stages of FDIM or, in the case of (A), feline iridal melanosis. (D) Photomicrograph of the anterior surface of the iris showing the earliest stages of FDIM characterized by neoplastic cells extending into the iris stroma (arrows) and not just on the surface. If dysplastic pigment cells are confined to the anterior surface only, that defines feline iridal melanosis. However, these cells extend a short distance into the iris stroma defining early FDIM. (E) Low magnification photomicrograph of a feline iris in which the pigmented cells are only on the surface (arrows), therefore, melanosis.

Figure 9.45.

Metastatic FDIM. (A,B) Metastatic FDIM in the kidney and the liver. Metastatic disease, when it occurs, is most likely to occur in the abdominal cavity.

Figure 9.46.

FDIM, microscopic. The montage illustrates some of the histologic variability in feline diffuse iris melanoma. (A,B) Examples of round and polygonal cell tumors, the most common types. (C) Spindle cells. (D) Balloon cells, common as individual cells or in small clusters, and, more rarely, as whole populations of cells. (E,F) Anaplastic tumors with multinucleate forms.

Figure 9.47.

Feline atypical uveal melanoma. (A) Gross photograph showing atypical ocular melanoma in a cat. The tumor is darkly pigmented and multifocal. (B) Subgross photomicrograph of feline atypical ocular melanoma showing extensive and multifocal involvement with extension well beyond the sclera. (C) Low magnification photomicrograph showing the characteristic involvement of the RPE in feline atypical ocular melanoma. (D) Photomicrograph of a bleached section showing the characteristic bland tumor cells with a round profile and bland-appearing round nuclei.

Uveal epithelial tumors

Irido-ciliary epithelial tumors in dogs (Figs 9.48, 9.49)

Figure 9.48.

Canine irido-ciliary epithelial tumors, clinical. (A) Japanese Akita, 8 years old: a pink vascularized ciliary body adenoma is present. (B) Beagle, 10 years old: the white cauliflowered mass was diagnosed as an irido-ciliary adenoma. (C) Mixed Breed, 8 years old: the anterior chamber is filled with a yellow-pink mass with hemorrhage. This was diagnosed as a ciliary body adenocarcinoma. (D) Poodle, 10 years old: the ciliary body adenocarcinoma totally occluded the angle superiorly. Strands of hemorrhage are present on the corneal endothelium. (E) Boston Terrier, 6 years old: both the apigmented mass inferiorly and the pigmented mass (arrow) arising from the posterior iris were diagnosed as a ciliary body adenoma. (F) Cocker Spaniel, 12 years old: detail of the anterior segment is concealed due to the corneal edema and vascularization. The ciliary body adenoma can be seen adjacent to the cornea (arrow).

Figure 9.49.

Canine irido-ciliary epithelial tumors, gross pathology. A montage of 25 dog eyes showing the variations in the gross appearance of irido-ciliary epithelial tumors. The characteristic feature is to fill the posterior chamber and cradle the lens. The tumors can be pigmented or non-pigmented.

There are 718 cases in the COPLOW collection, accounting for 12.5% of canine neoplastic submissions

• •Tumors of the irido-ciliary epithelium are the second most common primary ocular neoplasm in dogs
• •
  The signalment of affected dogs represented in the COPLOW collection may be summarized as follows:

  • ▪
    The average age of affected dogs is 8.2 years
  • ▪
    Affected dogs by gender (where known):

    • –
      Males: 83
    • –
      Neutered males: 274
    • –
      Females: 34
    • –
      Spayed females: 288
  • ▪
    There are 113 Golden Retrievers and 165 Labrador Retrievers, with this breed accounting for 39% of cases
• •Irido-ciliary epithelial tumors can arise from either the non-pigmented or pigmented epithelium of the ciliary body or, less frequently, the iris
• •Irido-ciliary epithelial tumors often present because of a pink, tan or pigmented mass in the posterior chamber or anterior chamber
• •The main differential considerations are melanocytoma and malignant melanoma
• •Clinical diagnosis may be complicated in cases with corneal opacity, intraocular hemorrhage, or other opacity of the ocular media
• •
  Other conditions that are frequently associated or concurrent with irido-ciliary epithelial tumors include:

  • ▪
    Neovascular glaucoma
  • ▪
    Intraocular hemorrhage
  • ▪
    Asteroid hyalosis, although generally considered to be of little clinical significance, is seen in association with 27% of canine irido-ciliary epithelial tumors
• •
  Classification based on invasiveness (Fig. 9.50 )

  • ▪
    Non-invasive adenoma

    • –
      These tumors are entirely confined to the posterior or anterior chamber and do not invade the substance of the uvea
  • ▪
    Uveo-invasive adenoma

    • –
      These tumors are still considered benign by morphologic criteria. Although they invade the uveal stroma they do not demonstrate scleral invasion
  • ▪
    Irido-ciliary adenocarcinoma

    • –
      Tumors which invade the sclera are designated adenocarcinoma by virtue of their invasive behavior; 116 cases in the COPLOW collection are classified as adenocarcinoma based on these criteria
    • –
      Adenocarcinoma has a more anaplastic morphologic phenotype than adenoma but is still not likely to metastasize
    • –
      The more aggressive and infiltrative the tumor, the more likely the neoplastic cells are to be positively immuno-labelled for cytokeratin as well as vimentin
  • ▪
    Pleomorphic adenocarcinoma (Fig. 9.51 )

    • –
      Very rarely, adenocarcinoma of the irido-ciliary epithelium is aggressively invasive, extending throughout the globe and infiltrating deeply into the orbit and into vascular structures
    • –
      There are 10 cases in the COPLOW collection and all of them are in eyes with a history of chronic disease, diagnosed as uveitis or glaucoma
    • –
      These tumors resemble the extremely rare human tumor, pleomorphic adenocarcinoma and they are likely to metastasize
    • –
      Usually stain with both cytokeratin and vimentin
• •
  Morphologic features of canine irido-ciliary epithelial tumors (Fig. 9.52 )

  • ▪
    Morphologic features of the epithelial cells

    • –
      90% of the neoplasms are predominantly non-pigmented, although about half of the tumors have some pigmented cells
    • –
      Degree of differentiation varies with biologic behavior
    • –
      Morphologic variants are:

      • ○
        Palisading ribbons, the most common pattern
      • ○
        Pleomorphic solid sheets
      • ○
        Anaplastic
  • ▪
    Morphologic patterns of the extracellular matrix

    • –
      60% of these neoplasms demonstrate thick, branching basal laminae, in a very distinctive pattern, which stain magenta with PAS stain in at least a portion of the tumor
    • –
      The remainder have thin basal laminae which subdivide cords, clusters, or sheets of neoplastic cells
  • ▪
    Many exhibit extracellular hyaluronic acid secretion

    • –
      This can be demonstrated by Alcian blue staining, before and after treatment of tissue sections with hyaluronidase
  • ▪
    Extracellular metaplastic bone is seen only rarely in canine tumors
• •
  Immunohistochemical profile:

  • ▪
    Vimentin positive
  • ▪
    Neuron specific enolase positive
  • ▪
    S-100 labelling is variable
  • ▪
    Cytokeratin labelling variable

    • –
      Benign irido-ciliary adenomas are often cytokeratin negative
    • –
      Overall, cytokeratin expression appears to increase with increasing aggressiveness of the neoplasm
    • –
      Cytokeratin 20 expression appears to decrease with increasing aggressiveness of the neoplasm
  • ▪
    TERT (telomerase reverse transcriptase) staining increases with increasing aggressiveness of the neoplasm
• •
  Pathologic features often seen in association with canine irido-ciliary epithelial tumors include: (Fig. 9.53 )

  • ▪
    Pre-iridal fibrovascular membranes (PIFVM)

    • –
      These can be associated with intraocular hemorrhage and/or neovascular glaucoma
  • ▪
    Asteroid hyalosis

    • –
      27% of dogs with irido-ciliary epithelial tumors also have asteroid hyalosis.

Figure 9.50.

Canine irido-ciliary epithelial tumors, invasiveness. (A) Subgross photomicrograph showing canine irido-ciliary tumor, which is not invading the uveal tract and exists entirely within the aqueous-filled posterior chamber. (B) Subgross photomicrograph showing an uveoinvasive tumor. (C) Subgross photomicrograph showing an adenocarcinoma, a tumor that invades both the uvea and the inner sclera. (D) A truly malignant canine irido-ciliary adenocarcinoma with features of the human pleomorphic adenocarcinoma.

Figure 9.51.

Canine irido-ciliary adenocarcinoma (pleomorphic adenocarcinoma). (A) Gross photograph of a highly malignant canine irido-ciliary adenocarcinoma (pleomorphic adenocarcinoma). (B) Subgross photomicrograph of the globe in (A). (C,D) Photomicrographs showing the histologic appearance of pleomorphic adenocarcinoma using a PAS stain. The distinct sharply delineated basement membrane is often very regionally apparent. (E) Immunohistochemical stain for vimentin showing the characteristic positive staining. (F) Positive staining for cytokeratin, a feature seen more often in malignant tumors of irido-ciliary origin and less commonly in benign tumors.

Figure 9.52.

Canine irido-ciliary epithelial tumors, microscopic. (A) Photomicrograph showing the most typical features seen in canine irido-ciliary adenoma. Bland epithelial cells are arranged along thick but indistinct eosinophilic basement membrane structures (H&E). (B) Photomicrograph of an Alcian blue PAS-stained specimen from an area similar to (A). With PAS, the basement membranes stand out. The Alcian blue-positive extracellular hyaluronic acid is also characteristic (arrow). (C) Photomicrograph showing less-differentiated epithelial features in a case without the thick basement membranes. (D) PAS-stained tumor with thinner basement membranes than (B) and more cellular atypia than (A) or (B). (E) Irido-ciliary epithelial tumor with anaplastic cellular features including multinucleate cells. (F) Immunohistochemical stain for vimentin showing characteristic positive staining. Both benign and malignant tumors stain with vimentin, as does the native irido-ciliary epithelium. (G) Immunohistochemical stain for cytokeratin is positive, which is characteristic of the more anaplastic or invasive tumors. The benign tumors and the native irido-ciliary epithelial cells do not stain with broad-spectrum cytokeratin.

Figure 9.53.

Secondary features associated with irido-ciliary epithelial tumors. (A) Gross photograph of a canine globe with a pigmented irido-ciliary adenoma and prominent asteroid hyalosis (arrow). (B) Gross photograph of canine globe with irido-ciliary adenoma and asteroid hyalosis (arrow). (C) Photomicrograph showing asteroid hyalosis (Alcian blue PAS). (D) Photomicrograph showing preiridal fibrovascular membrane and ectropion uvea in a canine globe with irido-ciliary epithelial tumor (arrow).

Irido-ciliary epithelial tumors in cats

There are 103 cases of irido-ciliary epithelial tumors in cats (Figs 9.54 , 9.55 ) in the COPLOW collection. Together, these constitute 2% of the feline submissions and 3.7% of feline ocular neoplasms.

• •Irido-ciliary epithelial tumors are the fourth most common intraocular neoplasm in cats, following diffuse iris melanoma, lymphoma and post-traumatic sarcoma
• •
  The signalment of affected cats may be summarized as follows:

  • ▪
    The average age of affected cats is 9.1 years
  • ▪
    Affected cats by gender (where known)

    • –
      Males: 6
    • –
      Neutered males: 45
    • –
      Females: 1
    • –
      Spayed females: 39
• •Feline irido-ciliary epithelial tumors generally fill the posterior chamber, cradle the lens equator, and infiltrate the iris, ciliary body, anterior chamber, and rarely the inner sclera
• •
  Morphologic features of feline irido-ciliary epithelial tumors: (Fig. 9.56 )

  • ▪
    These tumors are almost always composed of non-pigmented epithelial cells
  • ▪
    They seldom contain cords or ribbons of epithelial cells; rather, they are composed of solid sheets of polygonal cells which can be difficult to recognize as being epithelial
  • ▪
    There is a delicate but very regular vascular stroma which subtly subdivides the tumor mass into small subunits, and is made more apparent with the PAS stain
  • ▪
    About 30% of feline irido-ciliary adenomas have metaplastic bone within the mass
  • ▪
    The solid sheets of tumor tissue are often interrupted by cavitated cystic spaces. Occasionally, the tumors are predominantly cystic.

Figure 9.54.

Feline irido-ciliary epithelial tumors, clinical. (A) DSH, 7 years old: the large pink vascularized ciliary body adenoma fills almost the entire pupil. (B) DLH, 9 years old: this irido-ciliary adenoma has extended through the angle and into the anterior and posterior chambers (arrow). Resulting hemorrhage is present in the anterior chamber inferiorly. (C) DSH, 9 years old: this irido-ciliary adenoma is extending from the posterior iris. The mass also resulted in a retinal detachment. (D) DMH, 11 years old: the irido-ciliary adenoma has invaded through the angle and into the iris stroma. Extensive vitreous hemorrhage prevented visualization of the fundus.

Figure 9.55.

Feline irido-ciliary epithelial tumors, gross. A montage of gross photographs of 12 feline globes with irido-ciliary epithelial tumors showing the variations of involvement. The tumors are characteristically white, fill the posterior chamber and cradle the lens.

Figure 9.56.

Feline irido-ciliary epithelial tumors, microscopic. (A) Photomicrograph showing the typical solid pattern of polygonal cells and scant delicate vascular supply (H&E). (B) The same case as (A) stained with PAS to show the characteristic pattern of thin basement membranes around individual cells or small cell clusters. (C) This case has more obvious epithelial cords and a pigmented background. (D) Photomicrograph showing metaplastic bone (arrows), which is a feature in about half of the feline irido-ciliary epithelial tumors. (E,F) Photomicrographs showing features of two more anaplastic irido-ciliary epithelial tumors. The tumor in (F) is composed of spindle cells.

Feline ocular neuroglial tumor (Fig. 9.57)

Figure 9.57.

Feline ocular neuroglial tumor. (A,B) Gross photograph and subgross photomicrograph showing the characteristic features of feline ocular neuroglial tumor. A solid white tumor extends from the choroid and grows into the center of the globe. (C–H) Immunohistochemical stains showing positive staining for GFAP (C), S-100 (D), synaptophysin (E), chromogranin A (F), desmin (G), and skeletal muscle actin (H).

This is a rare but distinctive neoplasm arising in the uvea of cats. There are four cases in the COPLOW collection.

Morphologic features

• •The tumor appears solid and white on observation at the time of gross sectioning
• •The tumor bulges inward, extending from the uveal tract
• • Histologically, the tumor is a spindle cell tumor with moderately anaplastic features
• •
  Immunohistochemical profile

  • ▪
    Melan A negative (an antigen expressed by melanocytes)
  • ▪
    GFAP positive (a marker for glial cells)
  • ▪
    S100 positive (indicative of a neural crest derivation)
  • ▪
    Synaptophysin positive (a protein associated with synaptic transmission and neuroendocrine function)
  • ▪
    Chromogranin A positive (a neuroendocrine secretory protein)
  • ▪
    Desmin positive (indicating muscle tissue differentiation)
  • ▪
    Skeletal muscle actin positive (a skeletal muscle isoform of actin)
• •
  The immunohistochemical profile suggests a neoplasm with neural, glial, and skeletal muscle features

  • ▪
    Skeletal muscle is a feature of teratoid medulloepithelioma in humans, however these feline tumors lack other features characteristic of medulloepithelioma.

Medulloepithelioma (Figs 9.58, 9.59)

Figure 9.58.

Canine medulloepithelioma, clinical. (A) English Springer Spaniel, 2 years old: the whitish pink mass (arrow) has displaced the iris anteriorly. (B) Mixed Breed, 4 years old: a highly vascularized mass fills almost the entire pupil with fluffy white opacities. (C) Chow Chow, 9 years old: this large mass displaced the iris anteriorly. The histological diagnosis was medulloepithelioma or ciliary body adenoma. (D) Cocker Spaniel, 3 years old: the iris is dark and displaced anteriorly. The white mass (arrow) invading the iris added to the dyscoria.

Figure 9.59.

Canine medulloepithelioma, pathology. (A) Gross photograph showing a solid white medulloepithelioma filling approximately 60% of a dog's globe. (B) Clinical photograph of a dog eye with medulloepithelioma showing cavitated white tubes of neoplastic tissue in the anterior chamber (arrow). (C–E) Subgross photomicrographic images show medulloepithelioma in three dogs. (F) Photomicrograph showing the characteristic feature of cavitated tubes lined by a complex layer of elongated epithelial cells (arrow).

• •
  Medulloepithelioma is an ocular neoplasm in the general family of primitive neuroectodermal tumors (PNET)

  • ▪
    These tumors arise from different tissues that are derived from primitive neuroectoderm of the neural tube
  • ▪
    On the one hand, medulloepithelioma is closely related to irido-ciliary adenoma and on the other hand, the tumor shares many features with retinoblastoma (discussed in further detail in Ch. 11)

    • –
      Retinoblastoma is a common retinal neoplasm of humans but is exceedingly rare in domestic animals
    • –
      Irido-ciliary adenoma in dogs can have features typical of medulloepithelioma in segments of the tumor
• •
  Medulloepithelioma is a very rare tumor in dogs and horses, and is extremely rare in cats

  • ▪
    There are 29 cases in the COPLOW collection:

    • –
      24 in dogs
    • –
      2 in horses
    • –
      1 in a cat
    • –
      2 in other species (llama and goldfish)
  • ▪
    Isolated cases have been reported in other species, including birds and llama. However, reports are too sparse to allow an estimate of the prevalence of this neoplasm
• •
  Medulloepithelioma often occurs in young animals but there are many exceptions:

  • ▪
    For example, only 7 of the 24 canine in cases in the COPLOW archive are from dogs less then 5 years old
• •In dogs, the tumors usually originate in the ciliary body and can extend to involve the retina, whereas in horses some of the tumors originate in the optic nerve
• •
  Morphologic features of medulloepithelioma:

  • ▪
    The tumors are delicate, often multiple white masses, often within the posterior chamber, and they can be locally infiltrative
  • ▪
    Tumors often have papillary or botryoid extensions within the aqueous humor and, in some cases, can seed the anterior chamber with miliary, small nodular metastatic foci
  • ▪
    Tumors tend to show a pattern of survival around blood vessels with extensive necrosis away from vessels
  • ▪
    The hallmark histological feature is the formation of rosettes

    • –
      Flexner–Wintersteiner rosettes and Homer–Wright rosettes are also seen in retinoblastoma and other PNET Tumors and are not specific for medulloepitheliomas
    • –
      Larger, more complex multi-layered rosettes or tube structures lined by columnar neuroblastic cells are the defining feature of medulloepithelioma
  • ▪
    Although medulloepithelioma is locally invasive it is only rarely metastatic.

Comparative Comments.

• •Tumors of the retinal pigment epithelium and the epithelium of the ciliary body and iris are uncommon in humans and, in general, parallel the description given for other species. These may take the form of adenomas or adenocarcinomas
• •Medulloepitheliomas (dictyomas) are congenital neuroepithelial tumors arising from primitive medullary epithelium and are usually located in the ciliary body. Although some of these tumors appear histologically malignant, most have a relatively benign course if confined to the eye
• •Fuchs adenomas are benign proliferations of the nonpigmented ciliary epithelium. These are usually an incidental finding at autopsy or enucleation and rarely have clinical significance.

Uveal lymphoma and histiocytic neoplasia

Uveal lymphoma in cats (Fig. 9.60)

Figure 9.60.

Feline uveal lymphoma. (A) DSH, 11 years old: the temporal half of the iris is infiltrated resulting in dyscoria and a shallow anterior chamber. (B) DSH, 13 years old: the entire iris is infiltrated resulting in a posterior synechia and a fibrinous exudate in the anterior chamber. (C) DSH, 12 years old: the smooth pink elevation extends to the pupil margin temporally and nasally (arrow). (D) DSH, 8 years old: the generalized infiltrate in the iris has resulted in a severe dyscoria and in ectropion uvea (arrow). (E–G) Gross photographs showing the typical appearance of solid anterior uveal lymphoma. (H, I) Subgross photomicrographs showing solid uveal neoplastic infiltrates. The case in (H) involves the entire uvea. (J) Photomicrograph showing a monotonous population of neoplastic lymphocytes.

There are 284 cases in the COPLOW collection, accounting for 5.5% of feline submissions and 10% of ocular neoplastic submissions in cats

• •
  Uveal lymphoma is the second most common intraocular neoplasm of cats

  • ▪
    These cases do not include the round cell variant of feline post-traumatic ocular sarcoma (FPTOS). The round cell variant of FPTOS is distinguished from feline uveal lymphoma unrelated to trauma by its wide distribution in the globe, presence of lens capsule rupture, extent of necrosis and history. This tumor, which is also a form of lymphoma, is discussed in greater detail in Chapter 5 and later in this chapter.
• •The average age of affected cats is 9.8 years and there is no breed predilection. The FeLV/FIV status of affected cats is not often recorded in the COPLOW archive, however, there is no reason to believe that cats with uveal lymphoma are commonly infected by either retrovirus
• •
  Approximately half of feline uveal lymphomas are seen in combination with lympho-plasmacytic uveitis:

  • ▪
    The relationship between lymphoma and inflammation is not clear
  • ▪
    Lymphoma in association with uveitis is less likely to clearly express markers of T-cell or B-cell differentiation. However, these neoplasms are just as likely to impact lifespan/survival
• •
  Based on limited follow-up information available, uveal lymphoma generally represents a systemic rather than localized disease process. However, ocular disease is frequently the presenting complaint and may precede signs of systemic involvement

  • ▪
    This experience suggests that chemotherapy may be warranted in cats following enucleation of a globe that appears to be affected in isolation
• • The most common ocular tissue to be involved is the anterior uvea (iris and ciliary body). Uveal involvement may be nodular or diffuse. However, the retina, choroid, cornea (particularly the limbal region), adnexa, peripheral nerve tissue or optic nerve may also be affected
• •The ciliary body epithelium is often distorted by an infiltrate of neoplastic cells, a feature which may prove useful in making the distinction between lymphoma and melanoma, as melanoma is unlikely to specifically affect the ciliary body epithelium
• •
  Immunohistochemical labeling of leukocyte differentiation antigens and/or melanocytic markers can also help to distinguish between lymphoma and amelanotic melanoma

  • ▪
    There is not enough information to draw conclusions regarding the significance of immunophenotyping of feline ocular lymphoma. However, tumors of both T-cell and B-cell lineage occur.

Uveal lymphoma in dogs (Fig. 9.61)

Figure 9.61.

Canine uveal lymphoma. (A) Border Collie, 6 years old: nodular elevations of the iris (arrows) were present in both eyes with little aqueous flare. (B) Samoyed, 6 months old: two pink iris nodules are present. The miotic pupil is difficult to observe. (C–E) Gross photographs of canine globes showing the typical pattern of segmental invasion of the anterior uvea with lymphoma. (F–H) Subgross photomicrographs of canine globes showing segmental uveal infiltration by lymphoma. (I) High magnification photomicrograph showing anaplastic-appearing neoplastic lymphocytes in canine lymphoma affecting the eye. (J) Photomicrograph showing tumor in the ciliary body epithelium (arrows), a common finding in lymphoma, but rarely seen in other tumors.

• •
  Lymphoma is the third most common intraocular neoplasm in dogs

  • ▪
    There are 188 cases in the COPLOW collection, representing 1.3% of all canine submissions and 3.3% of canine neoplasms in the collection
  • ▪
    Ocular involvement is common in dogs with multicentric lymphoma
• •Ocular involvement is more likely to be bilateral in dogs than in cats, however bilateral cases are less likely to undergo enucleation
• •The anterior uvea is the most common tissue involved but lymphoma can also be recognized in the retina, cornea, adnexa, orbit, optic nerve head, or in peripheral nerve tissue
• •As is the case in cats, the ciliary body epithelium is often distorted by an infiltrate of neoplastic cells, a feature which may prove useful in making the distinction between lymphoma and melanoma, as melanoma is unlikely to specifically affect the ciliary body epithelium.

Intravascular lymphoma in dogs, malignant angioendotheliomatosis (Fig. 9.62)

Figure 9.62.

Canine intravascular round cell tumor. (A) Subgross photomicrograph showing a canine globe in which the uvea is distorted because of intravascular neoplastic round cells. (B,C) Photomicrographs showing neoplastic cellular infiltrate primarily within the lumina of uveal veins. (D) Immunohistochemistry showing positive staining for CD3 (T cells). (E) Immunohistochemistry showing positive staining for CD18, suggesting a macrophage phenotype. (F) Immunohistochemistry showing positive staining for MHC-II, again suggesting a macrophage phenotype.

There are six cases of intravascular lymphoma affecting the eye in the COPLOW collection, all in different breeds.

• •Intravascular lymphoma is a rare condition, characterized by primary neoplastic proliferation of lymphocytes within the lumen of blood vessels
• •
  The disease is systemic but the eye and the brain are common sites for involvement

  • ▪
    Clinical signs of ocular disease, including uveitis, panophthalmitis and retinal detachment may precede other signs of systemic involvement
• •
  Morphologic features of intravascular lymphoma

  • ▪
    Neoplastic lymphocytes fill widely dilated vascular spaces in the uvea
  • ▪
    Hemorrhage, edema, and infarction are seen in the tissues supplied by the affected vessels.
  • ▪
    Neoplastic cells can also spill over into the tissues near vessels
  • ▪
    This neoplasm does not form mass lesions.

Comparative Comments.

• •Lymphoma of the uveal tract in humans occurs almost exclusively in association with systemic malignant lymphoma
• •In addition, the choroid may be involved with lymphoid proliferation, either in association with systemic lymphoproliferative disease or as a primary ocular process
• •It is important to distinguish inflammatory pseudotumor from lymphoma on the basis of lymphocyte typing.

Histiocytic sarcoma and related tumors (Figs 9.63, 9.64)

Figure 9.63.

Histiocytic sarcoma, clinical. (A) Golden Retriever, 10 years old: the iris is heavily pigmented, but the white iris infiltrate can be seen superiorly (arrows). The masses in the eye and thorax were termed metastatic anaplastic spindle cell tumors. (B) Golden Retriever, 11 years old: the pink mass originated from the iris to fill the nasal anterior chamber.

Figure 9.64.

Histiocytic sarcoma, pathology. (A) A montage of gross photographs of 12 canine globes with histiocytic sarcoma showing the typical pattern of a large tan mass with extensive segmental infiltration in the globe. (B) High magnification photomicrograph showing the typical appearance of histiocytic sarcoma, including multinucleate giant cells with anaplastic features. (C) Subgross photomicrograph of immunohistochemistry showing positive staining for CD18, a marker for phagocytic cells.

• •
  Histiocytic sarcoma is a systemic canine neoplasm, in which ocular disease may represent the initial presentation

  • ▪
    Ocular involvement is typically unilateral
  • ▪
    The presenting signs frequently relate to uveitis, secondary glaucoma and/or the presence of an intraocular mass lesion
• •
  There are 54 cases in the COPLOW collection with a diagnosis of ocular histiocytic sarcoma

  • ▪
    In these cases, ocular disease was the initial presentation
• •
  This neoplasm has a strong breed-association. Of the 54 cases in the COPLOW archive:

  • ▪
    16 are Rottweilers
  • ▪
    18 are Labrador Retrievers
  • ▪
    20 are Golden Retrievers
• •Affected dogs often have other detectable masses or systemic signs that may be noted at the time of enucleation, or upon subsequent evaluation after histologic diagnosis of the ocular neoplasm
• •Life expectancy following diagnosis is very short
• •
  Morphologic features of histiocytic sarcoma include:

  • ▪
    A solid white mass segmentally effacing uveal tissue
  • ▪
    Neoplastic cells are pleomorphic, round or polygonal with abundant eosinophilic cytoplasm, cytoplasmic vacuoles, and multinucleate forms
  • ▪
    Positive by immunohistochemistry for CD18
• •
  Rarer than histiocytic sarcoma is systemic histiocytosis (Fig. 9.65 )

  • ▪
    There are 19 cases of canine systemic histiocytosis in the COPLOW collection
  • ▪
    Four are in Bernese Mountain dogs
  • ▪
    Ocular involvement is more likely to be episcleral or orbital than uveal
  • ▪
    Characterized by a more bland population of histiocytes, often with a vasocentric growth pattern

Figure 9.65.

Canine systemic histiocytosis. (A) Clinical photograph showing neoplastic mass lesion of systemic histiocytosis distorting the conjunctiva and lid tissues. (B) Subgross photomicrograph showing a canine globe and orbital connective tissues with systemic histiocytosis infiltrating the muscle and loose connective tissues of the orbit. (C) Photomicrograph showing solid sheets of rather bland histiocytic cells effacing the normal tissues. The prominent vasocentric pattern (arrows) is common in systemic histiocytosis. (D) Photomicrograph showing spindle-shaped bland-appearing histiocytes staining positive for CD18, a marker for phagocytic cells.

Spindle cell tumors of the iris in blue-eyed dogs (SCTBED) (Fig. 9.66)

Figure 9.66.

Spindle cell tumor of blue-eyed dogs (SCTBED). (A) Siberian Husky, 4 years old: a subtle loss of iris architecture nasally (arrows) was the only abnormality in this early case. The prominent iris pigment may have been congenital. (B) Siberian Husky, 4.5 years old: the inferior anterior chamber is filled with the iris mass, associated fibrin, and hemorrhage. (C) Siberian Husky, 7 years old: the limbal cornea is vascularized. The entire iris is infiltrated resulting in dyscoria and posterior synechia (arrow). (D) Australian Shepherd, 12 years old: this nasal mass was originally diagnosed as a neurofibrosarcoma of the iris. (E,F) Gross photographs of globes from two dogs with spindle cell tumor of blue-eyed dogs. (G) Gross photograph showing the scleral shell from a dog that had an evisceration in a globe with SCTBED. The tumor re-grew, leading to removal. (H) Photomicrograph of SCTBED showing a cellular arrangement typical of the Antoni B pattern of schwannoma (H&E). (I) Photomicrograph of a trichrome-stained SCTBED showing a delicate interplay between collagen (blue) and cellular cytoplasm (red). (J) Immunohistochemistry showing GFAP-positive staining, suggesting that the SCTBED is a tumor of the Schwann cells of non-myelinated nerve fibers.

• •
  There are 43 cases of spindle cell tumor of blue-eyed dogs in the COPLOW collection.

  • ▪
    This is a rare tumor type, accounting for only 0.7% of canine neoplastic submissions in the COPLOW collection
• •
  All affected globes, to date, have had a blue iris or, at least, a partly blue (heterochromic) iris

  • ▪
    Tumors identified in pigmented uveal tissue have occurred in animals with partly blue irides or, in one case in which the tumor was located in the choroid, a pigmented iris and non-pigmented choroid
• •
  The signalment of affected dogs may be summarized as follows:

  • ▪
    The average age of affected dogs is 7.5 years
  • ▪
    In the 43 cases identified, the following breeds are over-represented:

    • –
      Siberian husky (22 cases)
    • –
      Catahoula hounds (four cases out of a total of 15 Catahoula hounds represented in the COPLOW collection)
• •Ocular neoplasia was suspected at the time of submission in less than half of the cases in which SCTBED was diagnosed
• •The tumor is usually located in the iris, extending into the ciliary body, but there are also cases entirely confined to the choroid
• •The risk of metastasis is still undetermined. However, there are examples of tumors that have recurred in the orbit or within the scleral shell, following enucleation or evisceration, respectively
• •
  Morphologic features of SCTBED include:

  • ▪
    These tumors lead to a poorly delineated swelling most often within the iris stroma, expanding and distorting the uveal contour
  • ▪
    The neoplastic cells are spindle cells but they are highly variable in cellular morphology and cellular organization

    • –
      Individual cells range from small, slender spindle cells, devoid of anaplastic features, to large plump cells which exhibit karyomegaly and may be profoundly anaplastic
    • –
      The cellular organization may be consistent with that seen in peripheral nerve sheath tumors (Antoni A and Antoni B patterns)
  • ▪
    Immunohistochemistry of SCTBED

    • –
      Vimentin positive, suggesting mesenchymal origin
    • –
      S-100 positive, suggesting a neural crest origin
    • –
      GFAP positive in most cases

      • ○
        Although considered a marker of astrocytes of the central nervous system, Schwann cells of nonmyelinated nerves are also positively labeled for GFAP. For that reason the GFAP-positive immunolabelling of the majority of SCTBED cases provides strong evidence for a Schwann cell origin of this neoplasm
      • ○
        GFAP immunohistochemistry in unaffected, normal canine blue irides demonstrates a plexus of GFAP-positive fibers in the anterior iris and, to a lesser extent in other areas of the uvea, when compared with normal, pigmented iris tissue
    • –
      Melan A is usually, but not always negative indicating that the neoplasm is unlikely to be of melanocyte origin, which rules out spindle cell amelanotic melanoma
  • ▪
    There is a solitary, published report of a peripheral nerve sheath tumor with similar morphology in the eye of a dog, but in that report the uvea was pigmented.

Feline post-traumatic ocular sarcoma (FPTOS) (see Ch. 5 for detailed discussion of this neoplasm) (Fig. 9.67)

Figure 9.67.

Feline post-traumatic ocular sarcoma (FPTOS), pathology (A) Gross photograph showing spindle cell variant FPTOS. The tumor is distributed diffusely around the inside of the globe and extends through the sclera and into the optic nerve. (B) Subgross photograph showing spindle cell variant of FPTOS. (C) Gross photograph showing round cell variant of FPTOS. The pattern of diffuse infiltration within the globe and extension beyond the sclera is common to all three variants of FPTOS. (D) Gross photograph showing osteosarcoma variant of FPTOS. The globe has the same tumor distribution.

There are 234 cases in the COPLOW collection, making it the third most common intraocular tumor in cats.

There are three morphologic variants of FPTOS:

• 1.
  The spindle cell variant is most common (70% of FPTOS)

  • ▪
    The spindle cell variant is thought to originate from lens epithelial cells
  • ▪
    Extension beyond the sclera is a poor prognostic sign
• 2.
  The round cell variant (24% of FPTOS) (also discussed later in this chapter)

  • ▪
    The round cell variant is thought to be a lymphoma
  • ▪
    Phenotyping the round cell variant FPTOS has proven to be difficult
• 3.Post-traumatic osteosarcoma or chondrosarcoma (6% of FPTOS)

On average, there is a 7-year latency between a traumatic event with lens capsule rupture and the diagnosis of FPTOS.

Metastasis may occur by the following mechanisms:

• •Extension into the orbit leading to local recurrence
• •Extension along the optic nerve or peripheral nerves to the brain
• •Hematogenous metastasis
• •Rarely, metastasis to lymph nodes.

Metastatic neoplasia

• •
  Metastatic pattern in dogs (Figs 9.68 , 9.69 )

  • ▪
    Exclusive of lymphoma, there are 223 cases of metastatic neoplasia in canine eyes in the COPLOW collection, accounting for 3.9% of all canine tumors submitted in the COPLOW collection
  • ▪
    Neoplasms that often metastasize to the eye include histiocytic sarcoma, melanoma, hemangiosarcoma, osteosarcoma, mammary adenocarcinoma, as well as many others
  • ▪
    Common morphologic features of metastatic neoplasia in the canine eye include:

    • –
      Metastases may be present in one globe but recurrent tumor in the second globe is common
    • –
      A tendency to affect the anterior uvea more than the choroid
    • –
      Neoplastic cells are often identifiable in blood vessels
    • –
      Neoplastic cells ‘break out’ from the uveal stroma and ‘line’ the anterior or posterior chambers
    • –
      In some cases, thorough evaluation fails to reveal a primary neoplasm and diagnosis of a rare primary ocular malignant neoplasm, such as extraskeletal osteosarcoma or chondrosarcoma, may be made.
• •
  Metastatic pattern in cats (Figs 9.70 , 9.71 )

  • ▪
    Exclusive of lymphoma, there are 101 cases of metastatic neoplasia in feline eyes in the COPLOW collection, accounting for 3.7% of all feline COPLOW submissions with neoplasia
  • ▪
    Common morphologic features of metastatic neoplasia in cat eyes include:

    • –
      Uveal metastases may be recognized in one or both globes
    • –
      A tendency to affect the choroid more often than the anterior uvea
    • –
      When the anterior uvea is affected by metastatic epithelial tumors, the neoplastic cells form a ‘lining’ attached to the inner surface of the iris and ciliary body
    • –
      There is often extensive and widespread invasion of blood vessels
    • –
      A pattern of choroidal infarction is often seen, with characteristic, wedge-shaped areas of tapetal discoloration and profound vascular attenuation visible on funduscopy
    • –
      Orbital involvement may accompany involvement of the posterior segment of the globe
    • –
      Ocular metastases may be diagnosed in cats with many forms of malignant neoplasia; with pulmonary carcinoma, squamous cell carcinoma of undetermined origin, and fibrosarcoma being seen most commonly.

Comparative Comments.

Metastatic carcinoma of the choroid is the most common intraocular malignant tumor in humans. The most common primary site of choroidal metastases in males is the lung and in females the breast. These tumors may mimic amelanotic or lightly pigmented choroidal melanomas and are distinguished on the basis of history, systemic workup, fluorescein angiography, ultrasonography, and fine needle aspiration biopsy when necessary.

Figure 9.68.

Metastatic tumors to the eye, canine. (A) Golden Retriever, 11 years old: this was diagnosed as a metastatic hemangiosarcoma. In addition to the severe hemophthalmos, two areas of white infiltrate are present (arrows). (B) Skye Terrier, 10 years old: the blood-tinged white mass was diagnosed as a metastatic amelanotic melanoma. (C) A montage of gross photographs of six canine eyes showing metastatic tumors. These tumors are characteristically in the anterior uvea and anterior segment.

Figure 9.69.

Metastatic osteosarcoma case. (A) Australian Shepherd cross, 5 years old: severe corneal edema prevented visualization of anterior segment. Some 4 months prior to this photograph, a leg was amputated. Both globe and bone neoplasias were diagnosed as osteosarcoma. (B) Left eye of the dog in (A), 3 months later. The dark area at the pupil margin and the cloudy area inferior (arrows) represent retinal elevations. (C) Fundus photograph of the eye in Figure 9.69B. A misshapen optic nerve and superior temporal retinal elevation. Osteosarcoma was again diagnosed on histopathology. (D) Low magnification photomicrograph of the same dog as (A) shows osteosarcoma invading the uvea (arrows).

Figure 9.70.

Metastatic tumors to the eye, feline, fundus. (A) DSH, 13 years old: metastatic angioinvasive squamous cell carcinoma was diagnosed as the cause of the abnormal tapetal coloration and retinal edema. (B) DSH, 14 years old: a metastatic intestinal adenocarcinoma was diagnosed in the retina and choroid accounting for the sheets of gray discoloration (black arrow). The optic disc (white arrow) was also infiltrated. (C) DSH, 15 years old: a metastatic carcinoma was the etiology for the severe cellular infiltrate surrounding the optic disc (arrow). Tumors cells were found in the choroid, retina, and optic nerve meninges. (D) DSH, 17 years old: a metastatic adenocarcinoma of the sweat glands was the diagnosis of the choroidal and subretinal involvement, leading to the retinal detachment.

Figure 9.71.

Metastatic tumors to the eye, feline, pathology. (A,B) Gross photographs showing how metastatic tumors in feline globes characteristically involve the choroid with retinal detachment. (C) Gross photograph showing the posterior segment from a feline globe with chorioretinal metastatic pattern. (D) Gross photograph of a feline globe showing choroidal thickening associated with metastatic neoplasia. (E) Subgross photomicrograph of a metastatic epithelial tumor showing a line of basophilic metastatic tumor (arrow) surrounding the detached retina and the anterior uvea. (F) Photomicrograph from a primary lung tumor showing the angioinvasive nature of the tumor. A pulmonary artery is lined by neoplastic epithelium (arrows). (G) Photomicrograph showing the retina and choroid from a feline globe with choroidal angioinvasive metastatic carcinoma (arrows).