Tumors of the Eye

Tumors of the Eye

Richard R. Dubielzig

University of Wisconsin‐Madison, USA

Although tumors of the eye and its supporting tissues in domestic animals are relatively rare, they assume an enhanced importance because of the visibility and effect on function of even small tumors within, or adjacent to, the eyes. Because of the anatomic interrelationships between the tissues of the globe and adjacent tissues, such as lids and orbit, surgical removal of small tumors may not be an option. Although tumors within the globe may or may not be readily visible, their effect on ocular function can be dramatic, leading to visual defects, discoloration, discomfort, or a change in shape of the globe. These are the consequences of ocular neoplasia that cause an animal owner to seek veterinary attention.

Tumors within the globe present several unique problems to the pathologist. These tumors may be small and are often not apparent from the external surface of the extracted globe. Because the structures of the globe are delicate and the orientation of ocular tissues is important, the globe should be dissected free of extra tissue from the orbit and lids and immersed in fixative without opening the globe. Fixation prior to sectioning will enhance the rigidity of ocular structures and help maintain the ocular structures in their normal anatomic orientation. Table 20.1 summarizes the advantages and disadvantages of commonly used ocular fixatives. It is helpful if information regarding the location of the suspected intraocular tumor can be provided by the attending clinician prior to sectioning of the globe. Without this information, it is useful to have an apparatus that allows the pathologist to candle the globe. In a dark room, a bright light is situated in contact with the posterior sclera, illuminating the globe and revealing intraocular masses as dark shadows. The position of the mass should be recorded, and the section should be made to pass through the largest diameter of the mass. Ideally, sections of the globe should pass through the optic nerve and pupil; however, oblique sections are often required to assess neoplastic infiltration.

Table 20.1 Comparison of fixatives for ocular tissues

Fixative Contents Advantages Disadvantages
Formalin Formaldehyde Cheap, fast, good general fixative No serious disadvantages
Gluteraldehyde Gluteraldehyde Best for electron microscopy Slow penetration.Must open the globe for surface fixation
Davidson’s Formaldehyde, ethanol, acetic acid Added rigidity Shrinkage, not as good as formalin for EM
Bouin’s Picric acid, formaldehyde, acetic acid Added rigidity plus good for immunohistochemistry EM impossible, opaque yellow color, dry picric acid explosive
Zenker’s Mercuric chloride, potassium dichromate, acetic acid Best morphology with paraffin sections EM impossible.
Mercuric chloride is an environmental toxin


Most of the tumors of the haired skin of the lid are tumors generally found on the skin, and a list of expected tumors of the lid is given in Table 20.2.

Table 20.2 Skin tumors of the eyelids in domestic animals

Tumor Species
Meibomian gland Canine, feline
Sebaceous gland Canine
Squamous papilloma Canine, feline
Melanocytoma Canine
Mast cell tumor Canine, feline
Neurofibroma Feline
Trichoblastoma (basal cell tumor) Canine
Trichoepithelioma Canine
Sweat gland adenoma Feline
Basal cell carcinoma Feline
Sarcoid Equine

Tumors of meibomian gland origin


Meibomian gland tumors in dogs are comparable in frequency to their counterparts in sebaceous glands. They occur in increasing frequency as dogs age, and they invariably occur at the eyelid margin of either the upper or lower lid.1,2 Tumors of the meibomian gland are rare in cats.

Gross morphology and histological features

Meibomian gland adenoma is usually an exophytic, often papillary, protuberance bulging outward from the eyelid margin. Because the tumor contacts the cornea, ocular irritation, pain, and secondary keratitis or conjunctivitis may be a complicating factor. Meibomian gland adenomas are composed of well‐differentiated glandular tissue having a sebaceous appearance. Lipogranulomatous or lymphocytic inflammation around the exposed adenoma can contribute as much as or more to the mass effect than the tumor itself. Unlike sebaceous glands, macrophages surrounding meibomian gland adenoma or simply inflamed meibomian glands often contain intracytoplasmic refractile membranous bodies (Figure 20.1A–C), presumed to be ingested secretory material.

image described by caption.

Figure 20.1 (A) Clinical photograph of a canine meibomian gland adenoma. (B) Photomicrograph of an exophytic meibomian adenoma (arrowheads point to unaffected meibomian glands). A typical lipogranuloma (*) surrounds the deep margins of the tumor. (C) Photomicrograph of lipogranuloma showing macrophage cells. (D) Similar field to (C) viewed with polarized light showing birefringent material in the cytoplasm of the macrophage cells.

Meibomian gland epithelioma is analogous to sebaceous epithelioma and is composed of a larger proportion of basal cells, with a smaller proportion that have sebaceous or squamous differentiation. These tumors usually have a coexistent melanocytic component. Meibomian gland adenocarcinoma is a rare tumor which is more likely to be invasive and aggressive with local reoccurrence following incomplete excision.3 The exophytic component of meibomian gland tumors is often made up of a reactive papillary proliferation of stratified squamous epithelium which is not thought to be part of the neoplastic proliferation.

Conjunctival melanoma


Melanomas of the conjunctiva are rare tumors of dogs and cats (Figure 20.2). In 12 cases reported in dogs, there was a predilection for the tumor to arise from the nictitating membrane. Most of these tumors were cytologically malignant; local recurrence was a problem in over half of the cases, and metastasis occurred in two animals.4 Recurrent tumors, when they occur, develop on the conjunctiva but often in a different location. This might be explained by the tendency of these tumors to spread within the conjunctival epithelium by Pagetoid invasion of the epithelium. In cats, conjunctival melanomas are infrequent. When seen, they are often in the bulbar conjunctiva and extend deeply into the orbit near the sclera.

Photo displaying a globe and conjunctiva in a dog with conjunctival melanoma, with arrow pointing to a second affected area far from the large tumor.

Figure 20.2 The globe and conjunctiva from a dog with conjunctival melanoma. The arrow points to a second affected area far from the large tumor.

Gross morphology and histological features

These are nodular or multinodular masses distorting the conjunctival sac. They are sometimes amelanotic and often multifocal. The histological features of melanoma of the conjunctiva in dogs and cats are similar to those of malignant melanomas in other sites. These tumors have varying pigmentation and features of cytological atypia or anaplasia. Both pigmented and amelanotic tumors are malignant and the prognosis is not related to the degree of pigmentation. The mitotic count is presumed to be the best indicator of prognosis with more than 4 mitoses per 10 40× fields being considered malignant. Tumor cells tend to form tight aggregates, especially subjacent to or within the conjunctival epithelium. Tumors removed by broad excision or enucleation often show aggregates of intraepithelial neoplasm at sites distant from the primary neoplasm; this is called Pagetoid spread. Recurrent tumors often form at different sites in the conjunctiva. Amelanotic melanoma can be confused with anaplastic carcinoma, fibrosarcoma, or lymphoma, and differentiation is best made by immunohistochemical (IHC) staining. Melan‐A is reliably positive in conjunctival melanoma but other choices are used by other laboratories.

Tumors in cats are usually heavily pigmented and composed of large round cells and often multinucleate cells. They tend to extend deeply into the connective tissues adjacent to the globe.

Bovine squamous cell carcinoma


Ocular squamous cell carcinoma (SCC) is easily the most common and economically important neoplasm of the eye in cattle. Various studies put the incidence between 0.02 and 0.04%, as reported in a review of the topic.5

Geographic distribution

SCC is reported throughout the world. In the United States the tumor is more common in the southwest and areas with high sunlight exposure.5

Age, breed, and sex

SCC increases in incidence in older animals. Although all breeds are affected, Hereford cattle are the most frequently with an incidence estimated at 0.08%.5 The lack of pigmentation around the eyes is though to be a major contributor to the higher incidence in the Hereford but even excluding skin color, other genetic factors, as yet undetermined, contribute to the breed predilection.5 Although there is some disagreement there is no clear evidence that the sex of the animal is a risk factor.5

Gross morphology and histological features

The tumor most commonly begins on the lateral bulbar conjunctiva near the cornea (Figure 20.3). The lower lid and the nictitans are also common but the medial canthus is less common. Relative exposures to UV light is suggested to explain the high‐risk sites.5 SCC can be divided into four stages: plaques, papillomas, non‐invasive carcinoma, and invasive carcinoma.5,6 The plaque lesions are small and composed of hyperplastic and dysplastic epithelium. They have smooth margins and a raised surface and are translucent to opaque white. Histologically, there is epithelial hyperplasia with atypia and often hyperkeratosis. A papilloma is an exophytic growth which can be multiple and confluent. Non‐invasive carcinoma is thought to arise from the plaque lesion. This tumor has an exophytic outward irregular growth that distorts the ocular profile and causes pressure on the globe but shows little tendency to invade the scleral tissues. Invasive carcinoma shows both exophytic and invasive growth, with invasion of the deep subconjunctival stroma, sclera, and intraocular structures, but metastasis is rare. Microscopically, SCC exhibit highly anaplastic features, often with a concurrent desmoplastic response.5,6 In the experience of the author, the presence of a plaque indicates the early stages of a neoplastic process that could progress to papilloma, non‐invasive carcinoma, or invasive carcinoma; however, neither papilloma nor non‐invasive carcinoma progress into invasive carcinoma.

Photo of a globe from a bovine with limbal squamous cell carcinoma displaying tissue along the posterior aspect of the globe as a fat, connective tissue and muscle.

Figure 20.3 The globe from a bovine with a limbal squamous cell carcinoma (*). The tissue along the posterior aspect of the globe was not neoplastic, it is fat, connective tissue, and muscle.


The cause of ocular SCC in cattle is thought to be multifactorial. Familial lines of cattle with an extremely high incidence of the tumor have been reported.5 In most breeds of cattle, a lack of pigmentation around the eyelids is an important predisposing factor to the development of SCC. The tumor has a higher incidence proportional to the ultraviolet light exposure, and genomic damage related to UV light undoubtedly plays an important role in the pathogenesis of bovine ocular SCC.5

Equine squamous cell carcinoma


SCC is the most common neoplasm of ocular structures in horses.7 Although the incidence in horses is less than that in cattle, the biological behavior is similar. Tumors most commonly arise at the limbal conjunctiva or the nictitans as a dysplastic plaque and progress to varying degrees of invasive carcinoma. A hereditary predilection has not been demonstrated in the horse although the Appaloosa is overrepresented. Exposure to UV light is thought to be an important predisposing cause.

Gross morphology and histological features

As in cattle, the tumors appear as a plaque progressing to either non‐invasive or invasive carcinoma. Histologically the plaque consists of epithelial hyperplasia with or without hyperkeratosis.7 Disorganized elastin matrix suggesting actinic elastosis is often seen subtending the abnormal epithelium. There is usually an abrupt margin between the intraepithelial neoplasm and the surrounding normal structures. Invasive tumors have features of cytological anaplasia and desmoplastic stromal proliferation. Deep invasion of local tissues is seen, but metastasis is rare. An interesting morphological variant is the stromal invasive carcinoma (Figure 20.4A–D). These tumors show no exophytic growth but directly invade the corneal stromal lamellae, beginning as linear corneal opacities that expand and involve major portions of the corneal tissue without producing tumor‐like nodules. Spread beyond the cornea has not been reported.

Image described by caption.

Figure 20.4 (A) Gross photo of an equine globe with conjunctival squamous cell carcinoma spreading to the peripheral cornea and into the conjunctival substantia propria. (B) Subgross photomicrograph of the same case as (A). (C) Gross photo of an equine globe with corneal stromal invasive squamous cell carcinoma causing a marked thickening of the corneal stroma but no mass lesion outside the cornea. (D) Photomicrograph of an equine cornea with stromal invasive squamous cell carcinoma. Neoplastic epithelial cords are spreading deep within the lamellar corneal stroma (arrows).

Canine and feline squamous cell carcinoma

SCC of the conjunctiva, nictitans, and cornea of dogs and cats is rare and highly variable in presentation (Figure 20.5A,B) These tumors can be multifocal, exophytic papilloma‐like lesions, or aggressive infiltrating carcinomas with destruction of orbital tissue or penetration of the globe. Occasionally, SCC in dogs and cats occurs in conjunction with chronic inflammation of the conjunctiva. In cats, conjunctival SCC can be highly invasive into the orbit. Because these tumors are irritating and because deep local invasion is possible, enucleation is the treatment of choice. SCC of the canine cornea warrants a special mention.8 These tumors almost always occur on brachycephalic dogs with concurrent superficially oriented keratitis. Pugs are overrepresented even among these breeds. The tumors are usually axial on the cornea and seldom invade deeper than the superficial stroma so that they can be treated successfully by superficial keratectomy (Figure 20.6).

Image described by caption.

Figure 20.5 (A) Gross photo of a canine globe with squamous cell carcinoma infiltrating the substantia propria of the conjunctiva and deeply into the corneal stroma. Asteroid hyalosis bodies are floating in the vitreous cavity. (B) Gross photo of a feline globe with squamous cell carcinoma and similar involvement.

Image described by caption.

Figure 20.6 Gross photo of a canine globe showing a corneal squamous cell carcinoma involving the axial and superficial cornea. (B) Subgross photomicrograph of the same globe as (A).

Adenocarcinoma of the gland of the third eyelid in dogs and cats


Carcinoma of the gland of the third eyelid is a rare, sporadically occurring, invasive, solid neoplasm presenting as a mass lesion at the base of the nictitans on the ventromedial conjunctiva.9 The tumor displaces the globe, and in large tumors there is invasion of the adjacent orbital tissue (Figure 20.7A,B) Many of these tumors are low grade, however both recurrence and distant metastasis can occur in high‐grade tumors. Complex and mixed tumors can occur when myoepithelial cells are neoplastic, similar to other apocrine gland tumors (Figure 20.8). These tumors occur less frequently in cats but the prognosis is less favorable.9

Image described by caption.

Figure 20.7 (A) Gross photo of a canine globe and a mass lesion involving the gland of the third eyelid. (B) Subgross photomicrograph of the same globe as (A).

Image described by caption.

Figure 20.8 Photomicrographs of the same tissue illustrating the IHC staining pattern of a complex tumor of the gland of the third eyelid. (A) Cytokeratin, (B) vimentin, (C) SMA.

Histological features

These tumors are variable in morphology, with highly anaplastic and much more differentiated forms occurring. Complex tumors and mixed tumors with a myoepithelial component are often seen and truly mixed tumors with bone or cartilage are also possible but rare. Adequately excised tumors have a low recurrence rate, and metastasis is rare or non‐existent.

Feline conjunctival surface adenocarcinoma (mucoepidermoid carcinoma)


This is a rare but malignant tumor which is first detected as a raised, often papillated mass lesion of the feline conjunctiva.10 The tumor had been given the name mucoepidermoid carcinoma because of some similarities to a similar tumor of the conjunctiva in humans.10 However, mucin is not a major part of this tumor and the name conjunctival surface adenocarcinoma was adopted because it described the characteristic distribution and the type of differentiation. The most common original site is the third eyelid and that is because we believe that the tumor is from glandular duct epithelial cells, which extend out of the ducts to colonize the conjunctival surface. This tumor has great metastatic potential and spreads via the hematogenous route to distant sites.

Histological features

Characteristically these tumors are first noticed on the third eyelid as a surface thickening with a papillated appearance or as multiple nodules. They rapidly spread to other areas of the conjunctiva (Figure 20.9). Neoplastic nodules also become embedded in the conjunctival substantia propria; however, they display ductular or acinar features of glandular tissue. When sampled from the third eyelid, they can invade the gland and the relationship with the dilated ducts is then apparent.

Image described by caption.

Figure 20.9 Subgross photomicrograph showing the third eyelid from a cat with conjunctival surface adenocarcinoma spreading across the surface (arrows) and moderate stromal invasion (*).

Hemangioma and hemangiosarcoma of all species


Vascular endothelial neoplasms of the conjunctiva, nictitans, and even the avascular cornea are reported in several species, but they are seen most commonly in dogs, cats, and horses.11–14 In dogs, these tumors usually present as red, raised lesions of the conjunctiva, most commonly on the leading margin of the nictitans or the lateral limbus. Surgical resection of these tumors with clear margins is curative. Larger invasive lesions of the limbus or cornea can be difficult to resect, and as in subcutaneous tumors, the distinction between hemangioma and hemangiosarcoma depends upon the degree of cellular differentiation and local invasion. Aggressive tumors invade ocular tissues and mandate aggressive or extensive excision, including enucleation. In horses, there has been speculation that these tumors are of lymphatic vessels,12 but this interpretation is not clear. Vascular endothelial tumors of the ocular adnexa do not metastasize. Exposure to UV light may be a risk factor in the pathogenesis of vascular endothelial neoplasms.12,13

In dogs, the affected breeds are sporting breeds with nonpigmented conjunctiva and tend to originate in areas with sun exposure.

Histological features

In dogs, conjunctival vascular endothelial tumors are most often immediately under the epithelium and usually form an exophytic nodule. They are seldom difficult to diagnose. Hemangioma is distinguished from hemangiosarcoma by standard criteria, however neither tumor poses a risk of metastasis. In one study there was a slightly increased chance of recurrence of hemagiosarcoma locally13 (Figure 20.10).

Image described by caption.
Image described by caption.
Image described by caption.
Higher magnification micrograph of a tumor diagnosed as hemangioma displaying the neoplastic tissue abutting conjunctival epithelium.

Figure 20.10 (A) Gross photo of a canine globe with exophytic hemangiosarcoma in the temporal bulbar conjunctiva extending to the peripheral cornea. (B) Subgross photomicrograph of a canine globe with hemangiosarcoma in the bulbar conjunctiva under the third eyelid. (C) Photomicrograph of the tip of the third eyelid from a dog with hemangiosarcoma. (D) Higher magnification of a tumor diagnosed as hemangioma showing the neoplastic tissue abutting the conjunctival epithelium.

Conjunctival lipogranuloma of cats

This inflammatory condition causes a tumor‐like proliferative mass that may occur at any position in the conjunctiva of cats. Affected cats are usually old animals, and the disease is often bilateral. These lesions can be unilateral or bilateral, and the granuloma lesions have been reported to occur concurrently with invasive neoplasms.15 Lipogranuloma is refractory to medical therapy, but most cases respond well to surgical excision. Histologically, the lesion is composed of large extracellular pools of lipid surrounded by clusters of large macrophage cells, sometimes with giant cell formation (Figure 20.11). The conjunctival epithelium is usually intact over the granulomatous infiltrate. About half the cases have concurrent neoplasia and the risk of neoplasia should be a part of the comment on the biopsy report.

Image described by caption.

Figure 20.11 Photomicrograph of the conjunctival from a cat with lipogranuloma. The substantial propria is effaced by a granulomatous infiltrate composted of foamy macrophage cells including multinucleate giant cells (*). There are numerous empty spaces or lipid lakes (L). The epithelium remains intact.

Papillary conjunctival tumors of dogs


Benign papillary tumors are commonly found on the conjunctiva and, more rarely, on the corneal surface in dogs (Figure 20.12). These tumors are of three types: viral papilloma, reactive papilloma, and squamous papilloma. They are all focal tumors and benign, however they can induce local irritation and abrasion.

Image described by caption.

Figure 20.12 (A) Clinical photo of a dog with viral papilloma. (B) Photomicrograph of canine viral papilloma. (C) Clinical photo of a dog with conjunctival squamous papilloma of the conjunctiva. (D) Photomicrograph of squamous papilloma illustrating the fact that the papillary fronds are pointed (arrows). (E) Clinical photo of a dog with a reactive papilloma of the eyelid which is subtended by a meibomian gland adenoma. (F) Photomicrograph of a reactive papilloma of the conjunctiva subtended by inflammation. The papillary fronds are rounded (arrows).

Geographic distribution

Canine viral papillomas can occur on the mucosal surface of the conjunctiva or the corneal surface as well as the haired skin of the eyelid.16 They are most often seen in young dogs and can be multifocal. The oral cavity is the most common site of occurrence. There are rare reports of malignant transformation in the conjunctiva as well as other sites.17 Reactive papilloma is a papillary proliferative reaction, which is usually secondary to a coexisting tumor or inflammation. When seen on the lid margin it is usually seen as the superficial proliferation associated with a deeper meibomian gland tumor. When seen on the conjunctiva it is usually seen in combination with chronic inflammation. Squamous papilloma is always seen on the conjunctiva with no identified site predilection. It is not associated with any obvious coexisting pathology and does not express papilloma viral antigens.18

Gross morphology and histological features

Canine viral papilloma is characterized by an abrupt raised papillary proliferation sharply delineated from the surrounding normal epithelium of the conjunctiva, lid, or cornea. Characteristic features include extensive hyperkeratosis, a thick and jumbled basilar layer, and excessive keratohyaline bodies. Rounded and swollen epithelial cells, usually in the stratum granulosum, are a characteristic finding. Typically these tumors have a papillary exophytic growth pattern.

Squamous papilloma has delicate exophytic growths of normal‐appearing nonkeratinizing stratified squamous epithelium forming long narrow fronds, which end in a point. There is not an underlying pathology such as tumor or inflammation.

Reactive papilloma forms thick, rounded, and blunt fronds. The stratified squamous epithelium can have dysplastic features. The most common coexisting lesion is meibomian gland adenoma but chronic inflammation can also be seen with reactive papilloma.

The histiocytic proliferative disorders of the lids, conjunctiva, and globes of dogs


Proliferative histiocytic lesions are seen frequently in the conjunctiva, episclera, sclera, orbit, or affecting the globe (Figure 20.13). They will be discussed here because the most common of these, nodular granulomatous episcleritis (NGE), commonly presents as a mass in the conjunctiva. NGE is an idiopathic nodular proliferative lesion characterized by a solid mass that effaces the conjunctival substantia propria.19,20 The epithelium is intact and usually separated from the margins and the mass is not anchored to the epithelium. Most often these growths respond to immune suppression and disappear, so they are infrequently submitted to the pathology laboratory. Reactive histiocytic (sterile) proliferations are less confined and can occur anywhere around or within the eye. These proliferative reactions are invasive and destructive without naturalborders and can destroy the tissues in which they occur. They are seen in the eyelids, nictitans (especially in the gland), orbit, and invading all the tissues of the globe, and they can be bilateral. These mass‐like lesions are not considered to be neoplastic.

Image described by caption.

Figure 20.13 Schematic drawing and comments regarding the distribution and important features of primary tumors of the globe.

Histological features

NGE forms a distinct nodule under the conjunctival epithelium and is composed of a mixture of histiocytic cells and lymphocytes. Classical granulomas with necrotic or suppurative centers are not characteristically seen. The histiocytic cells can be very spindle resembling fibroblasts, which can make this tumor look like a sarcoma, but markers for phagocytic cells help to identify this tumor correctly. Some have used the term nodular fasciitis to define this morphologic variant. Others have found smooth muscle actin (SMA) in the spindle cells.21

Reactive histiocytic proliferative conditions are more aggressively infiltrating proliferative disorders without sharply defined margins and invade different tissue planes. Systemic histiocytosis in ocular and periocular tissues presents as solid sheets of histiocytes with a lesser lymphocytic component. The histiocytic cells can have a dysplastic cellular profile, making it hard to rule out histiocytic sarcoma. A characteristic, but not universal, feature is vasocentricity.


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Mar 30, 2020 | Posted by in INTERNAL MEDICINE | Comments Off on Tumors of the Eye

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