Tumors of the Eye and Ocular Adnexal Tissues

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NEOPLASIA

TUMORS OF THE EYE AND OCULAR ADNEXAL TISSUES William C. Rebhun, DVM

TUMORS OF THE CORNEA AND CONJUNCTIVA Squamous Cell Carcinoma

Squamous cell carcinoma (SeC) is the most common neoplasm of the equine cornea and conjunctiva. 1LJ, 32, lLJ, 62 sec and its precursors such as epithelial dysplasia and carcinoma in situ should be thought of as progressive pathologic conditions which start as nonneoplastic abnormalities (dysplasia) but may progress to neoplastic masses when neglected or modulated by a variety of intrinsic or extrinsic factors. Intrinsic factors that predispose to sec and precursor lesions include ocular pigmentation, age, gender, and genetics. Ocular and periocular pigmentation are the Inost obvious predisposing factors in that those horses having the least ocular pigmentation seem to have the highest incidence of sec. This is true for breeds such as Appaloosas, Paints, and Pintos. Nevertheless, Belgians, Shires, Clydesdales, and some other breeds have a high incidence of corneal and conjunctival sec despite having pigmented periocular skin and eyelid margins. lO , n This disparity is explained somewhat by the fact that the interpalpebra1 conjunctiva usually is nonpigmented in these draft breeds. Age is another intrinsic factor in sec, with most affected horses having initial signs between 7 and 10 years of age. 3LJ , 57 Age of onset is relative, however, because many horses are not diagnosed as having lesions for months or years following actual onset of the neoplasm or precursor lesions. Highlighting this range in age, the author has performed surgery on a 2-year-old Hafflinger and a 26-year-old Appaloosa for corneoconjunctival sec in the past year. Gender also may playa role in intrinsic predisposition to ocular and periocular sce, as Dugan et aPll reported stallions to be five times less likely and

From the Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York

VETERINARY CLINICS OF NORTH AMERICA: EQUINE PRACTICE VOLUME 14· NUMBER 3· DECEMBER 1998

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mares two times less likely to develop SCC than geldings. Genetic influences may be obvious (e.g., coat color, ocular pigmentation) or latent (e.g., geneticimmune determinants, equine leukocyte antigens). An increased understanding of risk for SCC should become available as the study of equine immunogenetics advances. Host responses to many extrinsic factors such as papillomaviruses, ultraviolet radiation, and parasites such as Onchocerca cervicalis, for example, probably are driven by genetic determinants. Extrinsic factors include ultraviolet radiation, chronic irritation or infection causing tissue metaplasia, possible viral infections of the tissue, and parasites. The most commonly discussed extrinsic influence of ocular SCC is ultraviolet radiation. Actinic influences are obvious clinical causes, because geographic regions having more sunshine and higher altitudes are likely to have an increased incidence of equine SCC. Viral infection of ocular tissues as a predisposing cause of SCC remains to be proven for horses but certainly deserves consideration from a comparative standpoint. Papillomaviruses have been linked to risk for ocular SCC in cattle59,60 and humans. 44 Others factors that possibly contribute to the risk of SCC include herpesviruses 41 and the human immunodeficiency virus. 33 Discussion of such viruses as extrinsic risk factors cannot be separated from the obvious intrinsic host genetic-immune determinants that influence the outcome of viral infection. For example, papillomavirus infection of the conjunctiva may either cause no disease or minimal neoplasia that responds favorably to any of a number of treatment modalities in animals that have appropriate genetic immune responsiveness to the virus. Chronic irritation or infection leading to tissue metaplasia with subsequent ocular SCC is best exemplified by horses that have neglected or recurrent conjunctival habronemiasis or onchocerciasis. Horses that have chronic conjunctivitis, chronic nasolacrimal duct obstruction, and congenital or acquired lid deformities are also at risk. The clinical signs of SCC and precursor lesions such as epithelial dysplasia are quite variable. Classic SCC of the cornea or conjunctiva appears as a pink, raised, cobblestoned mass that bleeds easily. Most tumors appear at the temporal limbal region, starting in the bulbar conjunctiva and then extending into the cornea (Fig. 1). Tumors may appear at any limballocation, however. Large (> 1.0 cm in diameter) obvious SCC that is pink, raised, and cobblestoned often has a white necrotic "cake frosting," allowing secondary bacterial conjunctivitis as well as a distinct fetid odor. Epithelial dysplasia, actinic lesions, and precursors ranging from dysplasia to neoplasia are most commonly observed in the temporal bulbar conjunctiva of the interpalpebral zone. These lesions have great variation in color and relative vascularity ranging from pink to white. Many appear as distinct pink or red lesions with a white raised surface that may be necrotic or dry and firm when dysplasia or precursor lesions exist. A rare form of epithelial dysplasia may appear as distinct corneal lesions that do not involve the bulbar conjunctiva. Corneal epithelial dysplasia appears as white or gray lesions in the periphery which may be singular or multiple. Superficial vascularization may extend from the limbus to the lesions. Initially resembling inflammatory infiltrate or scars, such lesions progress to raised, necrotic, loosely attached epithelial lesions with a dull gray surface. Such areas of dysplasia may progress to carcinoma in situ. Horses affected with epithelial dysplasia often have recurrence of lesions over a period of years. Recurrences may be at the original site or at new sites in the peripheral cornea. Treatment must be determined by the size and depth of the tumor, econom-

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Figure 1. Squamous cell carcinoma of the bulbar conjunctiva and cornea in a 9-year-old Appaloosa horse.

ics, past history or known recurrences, prior treatment (if any), suitability of the patient for general anesthesia (i.e., age, other medical conditions), and availability of treatment modalities. Early small lesions «1.0 cm in diameter) of minimal depth can be managed successfully by surgical excision, strontium-90 CmSr) beta radiation, radiofrequency hyperthermia, or cryosurgery. Larger lesions (> 1.0 cm in diameter) with a depth of more than 2 mm may require combinations of sharp surgery and adjunctive radiation, hyperthermia, or cryosurgery.lJ, 35, 49, 56 Judgment is essential to tumor management, and treatment must be tailored to the individual case. Some specific generalities include: • Sharp surgery. Conjunctivectomy and keratectomy should be perfornled with appropriate surgical instrumentation and magnification to facilitate complete removal of abnormal tissue. Adjunctive therapy should be directed towards areas of suspected margins and the limbal region, where the cornea and conjunctiva abut against a fibrous structure that prevents smooth surgical dissection from continuing from the cornea to the conjunctiva. Conjunctival lesions that require removal of more than 1.0 cm of tissue may benefit from covering by conjunctival suturing or grafting to prevent excessive granulation tissue from arising postoperatively from the scleral and episcleral tissue. Such granulation tissue may be confused with tumor regrowth but usually occurs more quickly (i.e., within 3 weeks). • YOSr beta radiation. Although excellent for small lesions having a depth of less than 1.0 to 2.0 mm, 4 0Sr beta radiation is limited in penetration of deep lesions. 16 A dose of 75 to 100 Gy per site is indicated. Excessive doses (e.g., total surface dose of >500 Gy) may permanently damage the corneal endothelium and cause deep corneal necrosis. Radiation with lJtlSr delays wound healing for approximately 7 days. Therefore, when using 90Sr in conjullction with sharp keratectomy, the need for addi tional postoperative healing time and treatment should be anticipated. • Cryosurgery. This is an excellent modality for small lesions and as an adjunctive therapy when used appropriately.56 Tumors of epithelial origin usually respond to temperatures of - 30°C. Proper instrunlentation and

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probes are essential lest excessive cryogen be delivered, causing permanent corneal damage. A double freeze-thaw-freeze cycle is recommended. Faster freezes and slower thaws facilitate cryodestruction. • Radiofrequency hyperthermia. This is good for small lesions with a minimal depth. Conjunctival tumors are easier to treat, because hyperthermia may cause corneal stromal necrosis if overdone. Treatment consists of applications that deliver tumor temperatures of 50°C for 30 seconds. 24 • Other treatment options may become available as research continues on alkylating agents such as topical mitomycin C (0.04<~)), which has been used to a limited degree for conjunctival and corneal dysplasia and neoplasia in humans.75 Success or failure of treatment for SCC and its precursors is greatly influenced by the size of the lesion at initial presentation. Success rates for small superficial lesions obviously are higher than for lesions greater than 2.0 em in surface area and greater than 2 mm in depth. Clinical reports that fail to document the size and depth of treated lesions are of limited value. Another humbling thought is that the host inflammatory and immune responses may influence outcome regardless of the treatment modality employed. Although such host response cannot be measured or predicted at this time, it probably relates to host immune responsiveness to viral and actinic pathology. For example, in humans, one third or more of surgically treated epithelial dysplasia lesions may resolve despite incomplete removal. 14, 25 The opposite is true as well, as some SCC does not appear to respond to any therapeutic modalities and progresses in a malignant fashion. In general, the prognosis for SCC of the conjunctiva and cornea is good for lesions less than or equal to 1.0 em in diameter and less than 0.2 em in depth. The prognosis worsens as size and depth of the tumor increase beyond these parameters, when tumors appear at multiple sites or when recurrence or metastasis is detected. Metastasis reportedly occurs in approximately 10(X) to 15
Other Neoplasms of the Cornea and Conjunctiva

Although rare, miscellaneous tumors of the cornea and conjunctiva such as hemangioma,S, 8,71 angiosarcoma,5,26 melanocytoma,2H mastocytoma,29,43 and lymphosarcoma 50 , 51 have been reported. Ocular tumors of vascular origin (i.e., hemangioma and angiosarcoma) deserve special consideration based on the dramatic signs and aggressive progression possible in some cases as cited in the references and observed in unreported cases. Any lesions suspected to be of vascular origin should be biopsied (excisional followed by cryotherapy if small) and treated aggressively if confirmed as such. Most tumors of vascular origin appear initially on the conjunctiva or nictitans but can advance to a size where definition of origin is precluded. Invasion of the globe and orbit and metastasis are major risks for angiosarcoma. 5, 26 Lymphosarcoma is the most common tumor of the hemolymphatic system in horses, usually is multicentric, and is capable of causing a multitude of clinical signs depending on the location of the major neoplastic infiltrates in

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each case. With the exception of the skin form, the disease is usually fatal. Ocular lesions of lymphosarcoma therefore tend to represent ocular manifestations of a systemic disease. Two of 21 horses confirmed to have ocular/adnexal lymphosarcoma had corneoscleral masses that appeared as smooth white or raised pink lesions. sl The smooth surface suggested a neoplasm other than SCC in these horses, but biopsy was necessary for a definitive diagnosis. Both horses had multicentric disease detected by a complete medical workup, but the ocular lesions were the original reason for referral. The possibility of non-SCC tumors of the conjunctiva and cornea needs to be considered despite SCC being so common. The value of biopsy before surgery in questionable cases or as a routine part of excisional histopathology in typical SCC cases cannot be overemphasized. Biopsy and histopathology allow accurate diagnosis and prognosis and help to avoid medicolegal problems when treatment is unsuccessful.

Congenital Tumors of the Cornea and Conjunctiva

Corneal and conjunctival dermoids are the major lesions in the congenital tumor category. Dermoids are uncommon in horses when compared with their incidence in dogs, cats, and cattle. Dermoids in foals may involve the cornea, bulbar conjunctiva, palpebral conjunctiva, or combinations of these three locations. The lesion is pigmented similar to the ocular and periorbital pigment and coat color of the foal. Dermoids are flat; have fine, short, stiff hairs projecting from them (which are difficult to view grossly); and are irritating to the animal. Dermoids on the palpebral conjunctiva lead to corneal chronic superficial keratitis, ulceration, and pigmentation. Those of the globe cause mild to moderate blepharospasm, lacrimation, and photophobia. Lesions may be unilateral or bilateral. Dermoids have been observed as one of multiple ocular anomalies in foals but usually are found as a singular lesion. Treatment via keratectomy-conjunctivectomy may be difficult, as the lesions usually are deeply seated in the corneal stroma. Corneal scarring should be anticipated following dermoid keratectomy due to the depth of the lesion and the obvious necessity of complete removal lest hair follicles not be completely removed. Conjunctival dermoids are easier to remove but may require some blepharoplastic procedures or conjunctival suturing to close large conjunctival voids. Cryosurgical destruction of the mass and hair follicles is possible for small dermoids.

UVEAL, RETINAL, OPTIC NERVE, AND OTHER INTRAOCULAR TUMORS

Intraocular masses may be subclinical and detected as incidental findings or be the major reason for presentation of a horse. Such masses may be difficult to observe when associated inflammation or secondary corneal edema due to glaucoma or endothelial injury throws a smoke screen around the primary lesion. Ultrasonography has become a great ancillary aid to standard ophthalmic examination in such cases. Complete ophthalmic examination, ocular ultrasonography, aqueous fluid cytology, or solid tissue biopsy may be indicated as an aid to diagnosis.

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Melanomas

Pigmented mass lesions of the iris cause the most frequent concern regarding the potential for intraocular neoplasia. Fear of melanoma carries over from comparative oncology to the horse. Fortunately, intraocular or uveal melanoma is uncommon. Iris cysts are common in Warmblood breeds and are sporadic in other breeds but may be differentiated from melanomas by transillumination. Cystic lesions arising from the corpora nigra are more problematic, because the location of these lesions Inay not always facilitate transillumination. Nevertheless, the site of origin and tendency for multiple or cluster hypertrophy of such corpora lesions usually allow them to be differentiated from melanoma. Intraocular melanomas are not rare but are uncommon when compared to the frequency with which dermal and mucocutaneous junctional melanomas are observed in gray horses. It is important to consider the various histopathologic categories of melanocytic tumors in horses.?o The classic multiple tumor, slowly progressive, dermal melanocytoma is most common in a gray horse. These horses have multiple tumors, frequently have progressive lesions at the perineal or other mucocutaneous junctions, and may eventually have metastases to the lymph nodes, viscera, central nervous system, or other areas, including the eye. These horses usually are middle aged to older (i.e., 10-25 years old). More aggressive melanomas have been observed in younger horses which are not always gray. This is a completely different tumor type and more likely to result in a malignant course. As regards the eye and adnexa, these aggressive melanomas tend to affect the eyelids and are discussed under that topic (later in this article). When such neoplasms affect the uvea or intraocular tissue, early diagnosis is essential to avoid metastasis. Such cases usually necessitate enucleation once recognized as melanoma, but one case report of successful sector iridectomy has been reported. 37 Uveal melanomas in young to middleaged (5-15 years) horses (of any color) cause progressive intraocular disease and seldom are amenable to treatment that preserves the eye and vision. When observed early, a brown-black pigmented mass arises from the anterior uvea, usually the iris periphery but sometimes from both the ciliary body and iris. Peripheral iris masses may be hidden by corneal edema, as the mass injures the corneal endothelium (so that water is not excluded from the cornea), infiltrates the drainage angle (predisposing to glaucoma), or does both. Aqueous flare and hyphema are possible. Ciliary body or iris-ciliary body masses frequently distort the pupil shape and alter the lens position. Excellent examples of intraocular melanoma are described by Barnett and Platt. 2 Intraocular melanomas in young to middle-aged horses usually require enucleation to decrease ocular pain and attempt to save the animal from death due to the high likelihood of metastasis. Alternative treatment options would require early diagnosis and appropriate surgical treatment. Older gray horses with uveal and intraocular melanomas have slowly progressive loss of vision, intraocular inflammation or hemorrhage, a high tendency for glaucoma, and possibly unilateral or bilateral tumors. These horses almost always have other melanocytic dermal tumors, lymph node involvement, and tumors in other visceral locations. Treatment would be palliative to maintain the patient's comfort and would be limited to enucleation of painful globes. A complete medical workup would include radiographs, ultrasonography, nuclear scans, biopsies, and aspirates or collection of appropriate fluid (e.g., abdominal paracentesis) to evaluate the patient's overall condition fully and detect other visceral melanomas. Most older horses with multifocal disease are humanely destroyed, but some extremely valuable horses have been empirically treated with cimetidine22

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or an autogenous vaccine formulated from homologous irradiated melanoma cells and bacille Calmette-Guerin (BCG) mycobacterial purified cell wall products (K.A. leglum, VMD, personal communication, 1995). The author has never used these therapies for intraocular neoplasia but has used them for selected medical cases. A consensus of veterinarians suggests that the vaccine has been more useful to stabilize (but not cure) and perhaps shrink problem melanomas. Cimetidine has not appeared to be helpful for melanoma patients in our hospital, but this may be due to the advanced state of disease in many of our referral patients.

Lymphosarcoma

Intraocular lymphosarcoma masquerades as uveal inflammation that may be unilateral or bilatera1. 50 , 51 Therefore, the clinical course is one of uveitis that responds poorly or incompletely to appropriate anti-inflammatory and cycloplegic therapy. Because horses of any age can be affected with lymphosarcoma, the existence of uveitis in a young to middle-aged horse seldom causes concern for neoplasia, at least initially. A complete physical examination and ancillary procedures as directed by other patient problems may aid in detection of other tumor sites, because the eye rarely is the only organ involved in this multicentric disease. Lymphocytes obtained from tissue or exfoliative cytology of equine lymphosarcoma patients often appear mature and uniform rather than immature or blastic. Therefore, the aqueous cytology may not differ greatly from that obtained from a horse with immune-mediated uveitis. Fortunately, this intraocular manifestation of lymphosarcoma is rare, because definitive diagnosis can be difficult until other lesions (e.g., lymphadenopathy, visceral disease, weight loss) appear in the patient. The disease usually is fatal, and treatment for other than the purely cutaneous form of lymphosarcoma has not been successful in horses.

Medulloepithelioma

A rare intraocular tumor that is either congenital or has an extremely early onset in life has been described. 12, 54, 65 Arising from the neuroepithelium, these tumors tend to be white or white-yellow vascular masses and to grow slowly to fill the vitreous cavity or cause buphthalmos. A recent case treated by the author was a 3-year-old Standardbred filly purchased at a sale with an unknown history other than the fact that her left eye appeared enlarged and blind. A yellow vascular mass filled the anterior segment. Corneal edema coupled with the mass precluded further ophthalmic examination. The eye was buphthalmic and blind. Enucleation was performed, and the mass was subsequently found to fill the globe. Histopathology confirmed the mass to be a medulloepithelioma. Neither this tumor nor one prior confirmed medulloepithelioma that was enucleated 5-l has shown evidence of metastasis.

Other Uveal Tumors

Adenomas, adenocarcinomas, and other rare tumors are possible. These would be diagnosed and managed similar to melanomas.

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Proliferative Optic Neuropathy

A benign and usually unilateral vvhite tun10r ansIng from the optic disc and projecting into the vitreous humor has been docull1ented in multiple instances and referred to as proliferative optic neuropathy. The lllass usually is detected as an incidental finding during ophthalmoscopy in older horses. Some masses have smooth surfaces, although others are cauliflower-like in appearance. Larger lesions tend to be pedunculated at their site of origin in the optic disc and can waver in the vitreous humor with ocularmovelnents (Fig. 2). Smaller lesions tend to be more fixed. The rate of progression is unknown, because ocular complaints are not present and the discovery is incidental. Ocular inflammation is not present unless coincidental anterior segment (cornea, iris, etc) disease coexists and provokes ophthalmic exall1ination. Although it is generally found in older horses, the author has observed proliferative optic neuropathy in a 6-year-old horse. In another 26-year-old horse, a complaint of shying or apprehension in response to objects in the left visual field of the horse was raised by the owner. The owner had trained and ridden the horse for its entire life and was therefore extrelnely aware of the horse's responses during riding. Ophthalmic examination of the left eye confirmed a large proliferative optic neuropathy lesion arising from the optic disc. The mass was cauliflower-like, pedunculated, approximately 60(X) of the diameter of the optic disc in size, and wavered in the vitreous humor. The lesion was large enough to cast a shadow on the retina ventral to the optic disc and apparently caused a blind spot that explained the acquired shying. No other ocular abnormalities were observed. Only one other horse that had a large proliferative optic neuropathy lesion has had a visual complaint in the author's experience of approximately 12 cases. One could argue that subtle visual complaints would be unlikely to be detected, as many affected horses are old and

Figure 2. Proliferative optic neuropathy in a 20-year-old horse.

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not used for high-level performance. The histopathology of a limited number of cases has led to scientific disagreement regarding the origin of tumor, but most suspect it to be of Schwann cell origin. Iii, :=15,72

NICTITATING MEMBRANE NEOPLASMS Squamous Cell Carcinoma

SCC commonly affects the nictitating membrane (third eyelid) of horses. Epidemiological risk factors, intrinsic host detern1inants such as a nonpigmented leading edge of the nictitans, and extrinsic factors such as ultraviolet light exposure are identical to those discussed in the section on tumors of the cornea and conjunctiva. Horses having reduced ocular and adnexal pigmentation should be monitored for SCC of the nictitans on a regular basis due to the frequency of the occurrence of this neoplasm. In a Colorado State University series, 31 of 35 tumors of the nictitating membrane were confinued histologically as SCC.Y The same workers reported that of 147 horses having ocular or adnexal SCC, 28.1 (% had tU1110rs of the nictitating membrane, nasal canthus, or both. Y' Ill, II At Cornell University, 53 of 59 neoplasms of the equine nictitating membrane were confirmed as SCC (W.C. Rebhun, DVM, unpublished data, 1997). Signs associated with SCC of the nictitans include a full range of precursor lesions as well as typical pink, raised, cobblestoned see (Fig. 3). Early lesions representing dysplasia of the conjunctiva, epithelioma, or papilloma may appear as white or pink slightly raised or roughened lesions on the palpebral side of the nictitating membrane. Some early lesions have a white surface which varies from firm to cru11lbly in consistency. see usually originates from the palpebral side of the nictitating membrane. Neglected or undiagnosed tumors erode through the cartilage to appear on the bulbar side of the nictating membrane or erode away the leading edge of the tissue. Associated ocular signs of conjunctivitis, ocular discharge, and mild ocular discomfort (e.g., blepharospasm) develop as the tU1110r enlarges or if the tumor erodes sufficient nictitating membrane to create corneal conjunctival irritation or ulceration. Owners may be unaware of the tumor in horses with prominent eyes that tend to "hide" the nictitans or in tumors that originate nasal to the leading edge of the third eyelid. As with any see, early diagnosis is the best aid to successful n1anagement. Neglected cases are particularly dangerous, because tumor extension from the nictating membrane quickly involves the globe, medial canthus, medial orbital ligament, and bony orbit. Therefore, it is important to diagnose see of the nictating membrane while the membrane is freely moveable and not fixed by tumor extension to the globe or adnexal tissue and while there are definable tumor-free edges on the nictitans. Treatment of sl1lall superficial see of the nictitating membrane may be accomplished with cryosurgery, radiofrequency hyperthermia, local excision, or beta radiation. Unless the horse can be observed frequently postoperatively by a veterinarian, the author prefers to remove the entire nictitating membrane to both effect cure and reduce the stress and concern of the owner monitoring for possible tumor recurrence. Horses (and cattle) do well following excision of the nictitating n1embrane, and problems such as the keratoconjunctivitis sicca seen in small animals are seldom observed in horses that have undergone this surgery. Removal of the entire nictitating membrane and all of the T-shaped cartilage within is imperative, however. Incomplete removal of the cartilage can lead to

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Figure 3. Squamous cell carcinoma of the nictitans in a Quarter Horse.

medial canthal chronic irritation from the cut section end of cartilage. The author has treated two Belgian horses that developed see in the nasal orbit following incomplete removal of the nictitans performed by laymen. Tissue metaplasia from chronic irritation of the remaining cartilage appeared to be the cause of the tunlors. Following surgical removal of the nictitating membrane, systemic antimicrobials and nonsteroidal anti-inflammatory drugs (NSAIDs) at standard dosages are employed for 1 week, and topical broad-spectrum antimicrobials are applied to the eye three to four times daily for 14 days. Discharge of the yellow serous material from the medial canthus is typical for several days due to exposed orbital fat. This should be cleaned away gently with moist wipes prior to applying topical medications. The prognosis is good for horses treated by excision of the nictitating membrane when see has been diagnosed early. Owners should be taught to examine the opposite nictitating membrane, because horses having the tumor may develop the same lesion in the opposite membrane in years to come. Other Tumors of the Nictitating Membrane

Other tumors of the nictitating membrane are rare but worthy of mention, because the patient's prognosis may depend on accurate diagnosis of the tumor,

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and the known frequency of SCC sometimes tends to reduce consideration of differential diagnoses. The aforementioned Colorado State University series of 35 nictitating membrane tumors included 31 cases of SCC and 1 each of basal cell tumor, hemangiosarcoma, papilloma, and neurofibroma. CJ Other case reports include a sebaceous adenocarcinoma,3h lipoma/'3 and lymphangiosarcoma. 26 The author's series of 59 nictitating membrane neoplasms included 53 cases of SCC, 2 of adenocarcinoma, 1 of melanoma, and 3 of lymphosarcoma. One of the lymphosarcoma cases was a horse that apparently had primary lymphosarcoma of the nictitating membrane, subsequently had the opposite nictitating membrane removed and confirmed to be lymphosarcoma, and has survived for over 5 years without any evidence of multicentric lYlnphosarcoma or local recurrence. Interestingly, a similar case of primary lymphosarcoma of the nictitating membrane in a horse that remained tumor-free following complete excision of the nictating membrane was reported by Glaze et a1. 21 The authors observed that the lymphoid tumor of the nictitating membrane was diffusely infiltrative and smooth surfaced, thereby appearing grossly different than a typical SCC. This same diffusely infiltrative and smooth surface appearance was also typical of lymphosarcoma in the author's cases. Despite these two primary nictitating membrane lymphosarcoma patients, histopathologic confirmation of lymphosarcoma from any ocular or adnexal site should dictate a full medical workup and a guarded prognosis, as the ocular site seldom is the primary or only site of this multicentric disease.

EYELID NEOPLASMS

Eyelid neoplasms are the most common tUlnors of adnexal tissues in equine practice. Although case reports document many tumor types, this discussion focuses on see, the most common tumor of the equine eye and adnexa, and equine sarcoid, which is the most common skin tumor of the horse and frequently involves the eyelid and periocular skin. In fact, many equine skin tumors diagnosed as fibromas, fibrosarcomas, or neurofibromas based on the histopathology of biopsy specimens are equine sarcoids. This is not a criticism of pathologists but rather a point that can help clinicians and pathologists to obtain meaningful biopsy samples which include both epidermal and dermal components whenever possible. Limited biopsy specimens that contain mostly dermal con1ponents and consist of swirling patterns of connective tissue cells can be difficult to categorize and can be interpreted differently by different pathologists.

Squamous Cell Carcinoma of the Eyelid

Pursuant to the discussion of the tumor in the section on tumors of the conjunctiva and cornea, the same risk factors apply for eyelid sec. Appaloosas, Paints, Pintos, and some draft breeds are at risk due to nonpigmented lid margins and periocular skin. The Belgian draft horse, although at risk for see of the nictitans and corneoconjunctival region, has pigmented lid margins and seldom develops eyelid neoplasia. Clydesdales and Shires can develop SCC at any ocular or adnexal site. Other genetic determinants have been discussed, and the major extrinsic contributing factor is ultraviolet radiation. Eyelid neoplasms accounted for 22.8
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rado State University workers; 28.1 <~o of these 147 cases involved nictitans, nasal canthus, or both, and 27.5<% were found at the limbus. II The same workers found that tumor location influenced survival and that see tumors of the eyelid and orbit were associated with the poorest prognosis. These findings support the impressions of many ophthalmologists that eyelid see is an extremely serious problem which can advance, recur, or metastasize following treatment unless diagnosed early and treated appropriately. Eyelid see has multiple appearances ranging from precursor lesions such as erythematous raised plaque, moist erosive focal lesions of the lid margin, and white-gray firm or crumbly raised lesions to obvious see with pink or pink-red raised granular lesions of the eyelid or lid margins (Figs. 4 and 5). Eyelid see also tends to be erosive, especially if located at the lateral or nasal canthal region of the eyelids. Many middle-aged to older horses with nonpigmented eyelid margins have precursor plaques or erosions suggestive of dysplasia, epithelioma, or early see. Observant owners may be aware of these lesions, but most owners do not become concerned until an actual eyelid mass or erosive lesion of the eyelid margin develops. A tentative diagnosis can be reached in most cases based on the typical appearance of the lesion in a lightly pigmented or nonpigmented lid surface. Biopsy is indicated for confirmation. Biopsy is essential when prior treatment has failed to control the lesion, a lesion has recurred, or multiple sites are involved. Physical examination, palpation of regional lymph nodes, and inspection of other anatomical areas such as mucocutaneous junctions of the sheath, penis, perineum, vulva, and lips should be performed. The differential diagnosis for eyelid see includes habronemiasis, equine sarcoid, and a number of less common tumors that require biopsy for diagnosis. Equine sarcoids that have eroded through the epidermis to appear ulcerative, raised, and granulomatous are sometimes difficult to differentiate from see by gross inspection. Habronema

Figure 4. Raised, erythematous eyelid margin lesion typical of epithelial dysplasia, precursor, or early squamous cell carcinoma lesion in an Appaloosa horse.

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Figure 5. Medical canthal squamous cell carcinoma in an Appaloosa horse. Note that the lesion consists of both erosive or ulcerative components as well as raised masses.

granulomas of the eyelid usually are red and granulomatous but may appear either ulcerated or raised. These parasitic granulomas are seasonal and often contain yellow-white nodules that appear mineralized. Granulomas due to Actinomyces, Phycon1ycetes, or other unusual organisms also would be included in the differential diagnosis in some geographic regions. Treatment of eyelid see depends on the size of the lesion, location of the lesion, success or failure of prior treatments, economics, and availability of treatment modalities to the veterinarian or referral center. Many treatments have been used successfully but some of these are not available to practicing veterinarians or clinicians at referral centers. The prognosis is better for small lesions than for large (> 1.0 em in diameter) lesions, and preservation of the functional integrity of the eyelid and eyelid margin is of paramount importance lest secondary corneal pathology occur following treatment. Treatments that preserve as much normal tissue as possible are most appropriate. Sharp surgery alone is seldom indicated. Treatment options include cryosurgery, radiofrequency hyperthermia, carbon dioxide laser ablation, interstitial radiotherapy, beta radiation COSr), chemotherapy via cisplatin in sesame oil injections, and excision plus or minus one of the prior adjunctive treatments. Small lesions less than 1.0 em in diameter and less than 0.2 em in depth can be managed successfully by cryosurgery, radiofrequency hyperthermia, beta radiation, or laser ablation treatment. Lesions with a surface area between 1.0 and 2.0 em and with a depth greater than 0.2 em usually can be treated by cryosurgery, laser ablation, interstitial radiotherapy, cisplatin serial injections, or radiofrequency hyperthermia, although this latter treatment may require reassessment and repeat treatment, because the technique is best suited for small lesions. Large lesions that are greater than 2.0 em in surface area and greater than

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0.2 cm in depth require careful consideration of treatment options, availability of various options, and a guarded long-term prognosis. Enucleation or exenteration may need to be considered in the worst cases. The following comments summarize the literature and the author's experience with various treatment options. Cryosurgery

Judicious cryodestruction of SCC kills neoplastic cells and may stimulate the local immune system to further reject or destroy neoplastic cells and help to preserve normal lid tissue and lid margin. 27,]O Appropriate instrumentation and thermocouples help to ensure proper freezing and result in less destruction of normal tissue. A double freeze-thaw-freeze cycle that attains freezing of the tumor at - 30.0°C and a margin of 0.5 to 1.0 cm of healthy tissue peripheral to the tumor is desirable. Faster freezing and slower thawing improves cryodestruction of the tumor but may be impeded by the highly vascular eyelid anatomy or tumors that bleed easily. Therefore, chalazion clamps may be helpful to act transiently as a "tourniquet" for the selected site. Thermocouples and controlled cryogen delivery are essential for effective killing of the tumor and cosmetic results. Excessive runoff or delivery of liquid nitrogen that is not controlled leads to excessive cicatricial damage. Adequate anesthesia is necessary and may be locat topicat or general depending on the size and location of the tumor. Postoperatively, the area becomes swollen, edematous, erythematous, and painful. The acute tissue reaction stabilizes by 24 to 48 hours postoperatively. As transudates ooze from the site, crusts or scabs may form on ulcerative surfaces. These crusts usually are harmless but sometimes can create corneal contact with subsequent abrasion or ulceration. Topical antibiotic ointments applied to the eye several times daily help to lubricate and protect the cornea against necrotic lid tissue. Warm compresses are useful to reduce lid edema when large tumors have been frozen. Although infection is rare, it can occur in cryosurgical wound sites. Infection only occurs with large tumors, where postoperative crusting of transudates and exudates traps bacteria. This is similar to the case with infections encountered in burn patients, where bacteria flourish under the eschar of a skin burn. Because infection can occasionally occur, monitoring the wound, cleaning it gently should excessive crusting occur, and the occasional use of systemic antimicrobials in selected cases may be necessary. Sloughing of frozen tissue occurs over 1 to 2 weeks; healthy granulation tissue and progressive epithelization then occur at the wound site. The larger the wound, the longer is the healing time. Hair is depigmented at the site (owners should know this before surgery), and some skin depigmentation should be anticipated as well. Radiofrequency Hyperthermia

Radiofrequency hyperthermia has found Widespread use for treatment of SCC in cattle, but it is also effective for properly selected equine SCC patients. 24 Hyperthermia is best applied to superficial or shallow see lesions that have a depth of less than 0.2 to 0.5 cm. Surface area is less important than depth when using this technique. The commercial device (RF-Thermoprobe, Hach Chemical Co., Loveland, CO) is designed to achieve heat of 50.0°C when applied to approximately 1.0 cm of tumor for 30 seconds. This treatment option is especially

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attractive for small superficial tumors and precursor lesions of the eyelids. Postoperative treatment and complications are similar to those of cryosurgery.

Beta Radiation Delivered by Strontium-gO Source

Limited to superficial tumors «0.2 em in diameter) and as adjunctive therapy following keratectomy, conjunctivectomy, or lid sharp surgery, beta radiation delivered by a '-)(lSr source l6 (Strontium90 applicator, Amersham International, Buckinghamshire, UK or Amersham Corp, Arlington Heights, IL) therapy is excellent when used appropriately. Minimal tissue irritation occurs due to lack of penetration, but visible hyperemia is obvious following topical application, and wound healing is delayed for approximately 1 week (author's observation) following radiation. Disadvantages are limited penetration, cost of the device unless it is likely to be used frequently, and the fact that patience and a steady hand are essential to deliver the desired dose over a period of 3 to 5 minutes. '-l°Sr contained within the tip has a long half-life and the instrument is effective for many years, but each year a longer application per site is necessary to deliver the desired dose. As discussed in the section on the cornea and conjunctiva, a dose of 75 to 100 Gy per 1.0-cm site is desirable as is slight overlap for multiple applications. Excessive beta radiation has caused permanent corneal damage by injuring the endothelium. Repeated multiple treatments over a prolonged time may cause delayed corneal healing or dystrophic changes. In their original paper, Frauenfelder et al l6 recommended 25,000 rads (250 Gy) per site with an 89(~) success rate and no reports of complications. Superficial eyelid sec is treated with 75 to 100 Gy per site but probably would be able to tolerate slightly higher doses without serious complications.

Interstitial Radiotherapy

Due to stringent state radiation hazard laws, our clinic has not been able to use interstitial radiotherapy for over 15 years. Nevertheless, this therapy, where available and delivered appropriately, can be an effective treatment for periocular tumors in horses. Various isotopes, including cesium 173, radon 222, gold 198, and iridium 192, have been used. 17, 6H, 73, 74, 77 Each state has specific radiation hazard laws that must be satisfied if such treatment is considered. In general, the treatments are extremely expensive for several reasons: isolation of the horse during decay of the radioisotope, cost of the therapy, cost of the radiation biologist or oncologist or of the radiologist and surgeon, and prolonged biological isolation of the patient depending on state law. Perhaps the best indication for interstitial radiotherapy is the patient with extensive SCC of the eyelid that is inoperable or untreatable with other options which would likely destroy the eyelid anatomically or functionally. Therefore, despite potential complications, including lid fibrosis, cataract formation, corneal injury, epilation of hair, and poliosis/K interstitial radiotherapy may be the only option for certain tumors inoperable by other means due to the depth and extent of eyelid involvement. When expense is not a problem, select cases may benefit from referral to a specialty center where this treatment is available.

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Carbon Dioxide Laser Ablation Available only at certain referral centers, carbon dioxide laser ablation has been used successfully to treat limbal sec and could be used for selected lid tumors as well. 13 Expense and availability of such lasers currently limit case experience with this modality. Intralesional Chemotherapy with Cisplatin in Sesame Oil Serial injections of cisplatin in sesame oil have proven to be an effective treatment for equine sarcoids, sec, and squamous cell papillomas. 69 Four treatments at 2-week intervals were used in the primary study.hL) Clinical impressions at multiple referral centers have been favorable since the original report of this treatment, but the proper mixture of cisplatin and sesame oil is not easy and presents logistical problems when handling a chemotherapeutic drug. In addition, relapse rates tend to be higher for sec patients than for sarcoid patients. Other complications, including local infection, are possible and would be similar to those of any technique requiring injection and subsequent chemonecrosis. Sharp Surgery Small lesions can be removed by sharp surgery if blepharoplastic procedures are employed to insure postoperative eyelid margin function and minimal cicatricial damage. In general, sharp surgery is not a top choice for sec tumors, except for those of the nictitating membrane and those on the cornea and conjunctiva that require keratectomy-conjunctivectomy. Sharp surgery may be a necessary component for large proliferative sec of the eyelid when adjunctive therapy also is employed. Whenever excision is considered, lid function and cosmesis must be maintained. Unfortunately, there is a high rate of recurrence of eyelid sec following surgical excision. If recurrence does occur, treatment options and outcome are compromised by the loss of lid tissue that accompanied the original excision. Sarcoid of the Eyelid The equine sarcoid of the eyelid is the most common skin tumor of the horse. 67 Due to the frequency of the tumor at various anatomic locations, including the head, periocular sarcoids often are encountered in practice. The causes of equine sarcoid are multifactorial, and the pathogenesis of these tumors has application for those interested not only in oncology but also in infectious disease, immunology, genetics, medicine, and surgery.42 There is a well-established basis for bovine papillomavirus (BPV) types I and II as the instigating cause of equine sarcoids. 42 ,66 Strains of BPV have been found to be identical in both cattle having papillomas and horses having sarcoids within a defined geographic area. 4h Exposure to BPV I or II does not automatically cause a horse to develop equine sarcoids, as individual genetic predisposition also is required. Genetics, specifically the major histocompatibility complexes, and other determinants play a major role in sarcoid risk. Equine leukocyte antigens occurring in individual and genetic lines of horses with sarcoids have been studied by Lazary et al,40

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Gerber and Antczak (in Switzerland),211 and Antczak and his colleagues in the United States-t2 for several years. Further work adds support to this strong genetic-imn1une relationship regarding the predisposition to and incidence of equine sarcoids in horses having specific equine leukocyte antigen types. 6 , 7, -to A breed predisposition to equine sarcoids has been shown, with Standardbreds seldomly affected, Thoroughbreds frequently affected, and other breeds affected at an intern1ediate rate.\ Many studies attempting experin1ental transmission of equine sarcoids, creation of equine sarcoids by inoculation or introduction of BPV I or II, homologous and heterologous transmission or transplantation of tumors, and other techniques can be sumlnarized as clinically confusing as regards results.-t2 The frustrating and variable results, despite the experimental design of these studies, can be explained by the new knowledge about the genetic-immune response to a nonhost virus. It is hoped that further work can elucidate clinically useful infonnation which may affect predisposition to this neoplasm. Extrapolation of this scientific work to the clinical arena helps to explain the variable course and response to treatment that varies from spontaneous regression to complete failure of multiple treatments encountered in equine sarcoid patients. Regardless of the data supporting genetic and immune predisposition to equine sarcoid, owners of horses having equine sarcoid want the animal treated. Therefore, proper diagnosis, treatment, and prognosis are the responsibility of the veterinarian. Horses usually develop equine sarcoid lesions when they are between 4 to 7 years of age, but they may be younger or older at first occurrence. Horse population and density may increase risk regardless of genetic and immune predisposition.~2The equine sarcoid is not malignant in the classical sense, that is, it does not metastasize or kill. The tumor borders are impossible to define by clinical means such as palpation and tend to be multiple. The tumor also tends to recur. These facts should be relayed to owners of affected horses prior to any treatment attempts. Equine sarcoid creates histopathologic abnormalities of the basal epidermis as well as the dermis; consequently, to obtain the most accurate diagnosis, samples of both tissues should be obtained at biopsy. A dense swirling fibrocytic dermal component is characteristic, and fingerlike dermal projections extend far from the definable or palpable mass. These histopathologic characteristics help explain the high failure rate of sharp surgery for treatment. Similar to sarcoids of other skin locations, eyelid sarcoids can present a multitude of gross appearances (Figs. 6, 7, and 8). Nodular nonulcerative, nodular ulcerative, multiple nodular, fibrous and raised granulomatous, and ulcerative excessively granulomatous tumors have been observed. In addition, minimally raised epidermal projections that appear wartlike, flat, alopecic, or crusty (flat sarcoid) are all possible. Therefore, any eyelid or periocular skin mass deserves biopsy confirmation prior to attempts at surgical excision. Because of the tumor's various gross appearances, the differential diagnosis list is extensive and includes see and other tumors, collagenolytic granuloma, excessive granulation tissue secondary to a wound of the eyelid, papilloma, epithelioma, parasitic granuloma, and ringworm. Sarcoids sometimes develop at the site of a skin wound, injury, or surgical incision (e.g., castration). Tumors that develop at skin wound sites are particularly difficult to control and tend to recur regardless of treatment. Biopsy of periocular sarcoids is extremely important for many reasons: • It establishes a diagnosis that directs treatment and prognosis.

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Figure 6. Nodular equine sarcoid in nasal canthal region of both upper and lower lid.

Figure 7. Raised, verrucous, and granulomatous-appearing equine sarcoid of the upper eyelid.

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Figure 8. Full-thickness eyelid sarcoid that developed subsequent to an eyelid laceration and proved to be extremely refractory to therapy.

• It should include, whenever possible, both epidermal and dermal samples of the mass. Obviously, ulcerated or granulomatous lesions may have lost the epidermal component and thus fail to satisfy this requirement. • It is medicolegally important, because sharp surgery treatment for equine sarcoid of the eyelid may constitute malpractice based on current scientific data. • Sarcoids occasionally worsen following biopsy or have granulomatous projections from biopsy sites. Alternatively, some regress following biopsy procedures. Owners should be warned of both possibilities, but because therapy should quickly follo\'v biopsy, this is not a major concern. Having submitted a biopsy, the clinician should be knowledgeable regarding the specific histopathologic characteristics of equine sarcoids that could make interpretation of the sample difficult for a pathologist. First, as previously mentioned, the equine sarcoid has both epithelial and fibroblastic dermal components. 31 When the epidermis is present, long tentacles of epidermis may project into the whirling clumps of fibroblasts or spindle cells of dermal origin. Fibroblasts always are close to the epidermis and are often perpendicular to the basal layer.3 1 Obvious compromises of this classic histopathologic description must be anticipated if the tumor in question is ulcerated or granulomatous or if the biopsy fails to include both epidermal and dermal components. The means of collection as well as the means of sectioning may further add confusion to histopathologic interpretation. Recognition of these variables as well as the individual opinions of pathologists reviewing the biopsies needs to be accepted by clinicians. Direct communication of clinical concerns to the pathologist is in

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order for eyelid neoplasms when equine sarcoid is considered. Having been privileged to work at a teaching institution, it has been this author's experience that the same biopsy may be diagnosed three different ways by three different pathologists. The pathologist is limited to the sample that is provided. Nevertheless, equine sarcoid may be easily confused with "fibroma," "fibrosarcoma," or "neurofibroma" depending on the sample submitted and the cut obtained for slide review. Fortunately, we are left with the same clinical treatment options for these tumors as for sarcoids, because the clinical behavior and treatment responses appear to be similar. The treatment of equine sarcoid may vary based on tumor location, tumor size, tumor number, time of year (insect complications), economics, and response to prior therapy, if any. Tumor cure or failure thereof is influenced by the treatment modality selected, persistence of treatment when multiple treatments are required, and the host response (local immune response) generated by treatments that stimulate host rejection. The clinician cannot correct geneticimmune predisposition to equine sarcoid but may suspect host deficiencies based on the history, prior treatment failure, or multiplicity of sarcoids. In addition, periocular sarcoids present a special problem as regards eyelid function. Treatment must address and anticipate any wound or cicatricial complications that could alter eyelid function as regards protection of the eye. Sharp surgery is not only highly unsuccessful for treatment of periocular sarcoids but also sacrifices or compromises the lid mass or eyelid margin that is so important to tear distribution and corneal health. Treatment modalities include the following options. Cryosurgery

Cryosurgery is excellent for defined singular masses of the periocular or eyelid region. Nodular masses may be frozen in situ. IS Ulcerative or granulomatous masses may be debulked to skin level with electrocautery or carbon dioxide laser ablation to provide both reduction in size of the mass to be frozen and hemostasis. Freezing should employ a double freeze-thaw-freeze technique with the tumor and a surrounding I.D-cm halo of normal tissue. Thermocouples are helpfUl to ensure that the tumor and margin are frozen to - 40.0°C to - 50.0°C as indicated for tumors having connective tissue components.7H As discussed, rapid freezes and slow thaws are conducive to the best cryodestruction. This is not always easy, as eyelids are quite vascular and ulcerative lesions tend to bleed excessively. Hemostasis is essential if debulking is required. It should be remembered that multiple eyelid masses, sarcoids that involve more than 50% of an eyelid surface, large periocular masses, and flat sarcoids are poor candidates for cryosurgery. In contrast, singular masses, small multiple masses, and pedunculated sarcoids that can be debulked to a smaller origin stem are excellent candidates. Cryosurgery not only causes cryodestruction of tumors but is thought to stimulate the local immune system by release of cellular protein from tumors, which allows better tumor recognition and rejection. Therefore, when faced with multiple sarcoids, it may not be necessary to freeze all tumors. Immunotherapy with Bacille Calmette-Guerin-Purified Protein Products

BCG is a Mycobacteriunz organism whose cell wall proteins have been purified and used to stimulate a nonspecific cellular immune response by injection of these products as a foreign protein into tumors such as equine sarcoid. 47, 48, 76

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Commercial products such as Nomogen (a Mycobacteriunz organism cell wall fraction immunostimulant produced by RIBI Immunochemical Research, Hamilton, MN, and distributed by Fort Dodge Laboratories, Fort Dodge, IA) may be injected into sarcoids at 2-week intervals until regression or sloughing of the tumor occurs. Usually two to six injections are necessary, and there is no defined number of injections other than that required by clinical response. This author has observed one full-thickness eyelid sarcoid involving the entire upper lid that did not appear to respond until the sixth and seventh injections, after which it regressed completely. Treatment depends on the host's local immune response to recognize the foreign protein (BCG) and the cells (i.e., sarcoid) containing it as abnormal. Injection is more art than science, as the reconstituted BCG is a viscous product suspension and sarcoids are dense fibrous tumors. This author explains to students that injecting BeG into sarcoids is like injecting clam chowder into a brick. Therefore, Luer-Iock needles and syringes are helpful, and dividing the vial contents into more than one syringe is indicated lest needle "blow off" causes costly loss of BCG. Approximately 1.0 mL of BCG should be injected per 1.0 to 2.0 em] of sarcoid. When multiple sarcoids are present, several may be injected. As is the case with cryosurgery, however, the local immunity that is stimulated by this therapy may cause regression of even noninjected tumors in those horses having multiple tumors. Postinjection edema and inflammatory swelling of the site occur within 24 hours, should be anticipated, and can be reduced with warm compresses and peri-injection treatment of systemic NSAIDs. Cisplatin in Sesame Oil

Local chemotherapy with intratumoral cisplatin suspended in sesame oil has been described recently as a treatment for equine sarcoids and other periocular tumors. oY Acute tissue edema and inflammatory swelling may follow the injection and may require symptomatic therapy with warm compresses and systemic NSAIDs. Steroids should be avoided, however. Tissue sloughing should be anticipated, but simple regression may also occur. The effect of this treatment on host local immune responsiveness to the treated tumor is unknown, but this modality should be thought of as chemotherapy. Carbon Dioxide Laser Ablation Therapy Popular in Europe42 and used for selected sarcoids worldwide, carbon dioxide laser ablation therapy allows very defined excision, hemostasis, and stabilization of tissue margins. Nevertheless, unless it stimulates the local immune response, the laser cannot define the extent of tumor margin any better than a sharp incision. Therefore, recurrence is possible, and the technique has many disadvantages when used for large eyelid neoplasms, especially sarcoids. Interstitial Radiotherapy or Brachytherapy

As discussed in the section on the treatment of eyelid SCC, interstitial radiotherapy with a variety of isotopes may be useful for the treatment of eyelid sarcoids. This technique may be especially indicated for eyelid tumors that have failed to respond or have worsened following other treatment options and for sarcoids that appear to have no other treatment options because of their size, location, or advanced state. 1Y21r has been used in a large number of equine periocular tumors with good progression-free rates. 6H As with any treatment, the

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results of this study showed the best success with smaller tumors. Complications include both lid cicatricial damage and direct ocular radiation toxicity. Treatment options should be discussed with owners based on the individual horse and on tumor size, location, and number. Cryosurgery may require general anesthesia and special equipment but offers the hope of a one-time treatment success. Injections of BCG require several repeat treatments, costly drug, and possible sloughing wounds. Injection site and patient nature determine appropriate sedation and anesthesia. Cisplatin is expensive, requires multiple treatments, is hard to reconstitute in sesame oil, and may be difficult for practitioners to prepare. Interstitial radiography is expensive and limited to referral centers that can handle radiation hazard requirements and equipment. Sharp surgery is probably contraindicated for eyelid sarcoids as may be carbon dioxide laser ablation, which is not widely available. Although many practitioners report occasional success with sharp surgery for equine eyelid sarcoids, the multitude of referral cases having histories of surgical treatment failure causes this author to not recommend sharp surgery. Various topical caustic or chemotherapeutic agents such as bichloroacetic acid and 5-fluorouracil have been reported to control or cure small equine sarcoids when repeatedly applied to the tumors. Although these reports are anecdotal, some practitioners claim fair to good success if treatment is started early. Melanoma of the Eyelid

Eyelid melanomas occasionally are encountered in horses, usually those with a gray coat color. The most common form of eyelid melanoma is the slowly progressive melanocytic tumor that is common to middle-aged and older gray horses. This neoplasm tends to be multiple and prefers mucocutaneous junction areas and other sporadic skin locations. Treatn1ent or control of this type of melanoma is frustrating due to its tendency for multiple tumor locations and slow progression and the failure of sharp surgery to cure existing tumors or prevent new tumor formation. Eventually, such multiple melanon1as metastasize, invade locally, multiply, or create visceral, neurologic, ophthalmic, or respiratory tumors that are fatal. The course is generally slow over a period of years, however. The other type of eyelid melanoma in horses is a much more aggressive tumor that tends to occur in horses under 10 years of age and may occur in extremely young horses. These tumors tend to be singular or multiple but confined to a relatively small anatomical area of the skin. The clinical course from first observation is rapid, and the tumor may more than double in size within a period of weeks. Aggressive melanomas involving the eyelid initially appear as skin nodules but progress to full-thickness tumors with obvious black tumor apparent on the palpebral conjunctival aspect of the mass. Unless a small portion of the eyelid is involved, sharp surgery appears to be contraindicated for local excision, because it is likely to remove excessive lid mass and margin, thereby compromising lid function and corneal health. Cryosurgery has been the preferred option for these aggressive melanomas of the eyelid in the experience of this author and others. 3R Melanomas that involve 75(~) or more of the eyelid may be impossible to control by any method without anticipated cicatricial complications, and these large tumors may require wide excision coupled with enucleation to both cure the tumor and prevent the eye from inevitable chronic pain due to eyelid dysfunction. Oral cimetidine has been used as a

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treatment for rapidly growing singular or multiple melanomas in horses. Although the mechanism of action is poorly understood, some clinical success has been claimed. 22 Unfortunately, the experience at our hospital has been that cimetidine as a sole form of treatment seldom controls or resolves aggressive melanomas in horses. Nevertheless, other clinicians do believe that oral cimetidine may be helpful for horses affected with melanomas, and such use as adjunctive therapy therefore cannot be discouraged. Experimental vaccination of horses having aggressive melanomas using a preparation of irradiated homologous tumor cells in BCG has controlled or caused some regression of tumors (K.A. Jeglum, VMD, personal communication, 1995). The treatment is expensive, because repeated injections at increasing intervals are part of the protocol. Nevertheless, this option should be considered when cost is not a major concern.

Other Eyelid Neoplasms

Biopsy confirma tion of eyelid tumor types other than SCC, sarcoids, and melanomas are uncommon but not rare. Adenomas, adenocarcinomas, mast cell tumors, basal cell tumors, hemangiolnas, hemangiosarcomas, lymphosarcomas, papillomas, and other tumors have been reported and must be considered individually when diagnosed by biopsy as to best treatment option. Each of these less frequent tumors must be evaluated as to size, location, magnitude of associated lid dysfunction or ocular irrita tion, and likelihood of local growth or metastasis. In general, connective tissue tumors such as fibromas, fibrosarcomas, and neurofibromas are treated similar to equine sarcoids, because the success of sharp surgery in control of the tumor as well as subsequent lid function is poor. Lymphosarcoma of the eyelid and palpebral conjunctiva is the most common ocular adnexal location of this usually multicentric neoplasm. 45 ,51 Early lymphosarcoma infiltration of the eyelid resembles simple eyelid edema with mild lid swelling and conjunctival chemosis. More advanced infiltration causes rubbery firm or hard diffuse lid masses which may involve one or multiple eyelids in the patient (Fig. 9). Biopsy confirmation dictates a complete medical workup to identify other tumor locations, because the ocular/adnexal tumor seldom is the only site of lymphosarcoma. Treatment is rarely an option in multicentric lymphosarcoma, although corticosteroids and other chemotherapeutic agents may be considered. Equine papillomas (warts) are benign tumors of the face in young horses. Multiple warts of the muzzle, nares, ears, eyelids, and occasionally other locations tend to be white, gray, or black typically raised and crusty papillomas. The tumors are self-limiting in horses less than 24 months of age unless the patient is immunosuppressed or has inherited or acquired immune deficiencies. A viral origin is supported by transmission and contagion among group-housed weanlings and yearlings that share common feed and water containers. Although many "folk treatments," including crushing warts and cutting off some warts, cryodestruction of some warts, and a host of topical drugs that are putatively successful are employed, most papillomas spontaneously resolve within 6 months and do not require treatment. Individual horses having warts that fail to resolve or worsen and cause discomfort should have medical workups to rule out immune deficiencies.

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Figure 9. Advanced lymphosarcoma of the eyelids and conjunctiva.

ORBITAL TUMORS

Orbital tumors may arise as primary neoplasms or be secondary to primary tumors of the maxillary and frontal sinuses. Orbital SCC may occur either from extension of ocular / adnexal SCC into the orbit or from extension of primary sinus SCC into the orbit. A variety of tumors have been found in the equine orbit,3' 4, 23, 34, 39, 51, 53, 64 and all carry a guarded prognosis. The majority of orbital tumors occur in older horses (frequently >20 years old), which further alters the prognosis and owner willingness to pursue therapy. Clinical signs of retrobulbar tumors usually include unilateral progressive exophthalmos with or without distension of the fossa caudal to the zygomatic process of the frontal bone, mild epiphora, and ocular discharge. Associated neurological deficits may include visual loss due to optic nerve dysfunction, efferent pupillary dysfunction from injury to the oculomotor nerve, or Horner's syndrome. Retropulsion of the globe may meet resistance. Severe exophthalmos may result in chemosis, exposure keratitis, and an inability of the eyelids to fully protect the cornea. Sinus masses that expand into the orbit are accompanied by obvious bony distension of the sinus and pain elicited by palpation of the involved bone. Orbital tumors originating from extension of ocular / adnexal SCC or hemangiosarcomas usually have obvious adnexal neoplasia accompanying the exophthalmos. 5,26 Sclerosing malignant SCC may occasionally involve the orbit in such a way as to cause loss of normal retrobulbar structures with subsequent enophthalmos and erosion of the orbital bone. Sinus tumors and tumors of respiratory epithelial origin may cause ipsilateral nasal discharge, fetid breath,

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or ipsilateral respiratory stridor and diminished nasal air flow. Lymphadenopathy may be present due to tumor metastasis or secondary infection of sinus neoplasms. The differential diagnosis includes orbital and sinus granulomas, infections, and cysts as well as rare conditions such as acute nutritional myonecrosis of the muscles of mastication resulting in bilateral exophthalmos. 5H,61 Severe jugular thrombosis or other vascular abnormalities also occasionally resul t in apparent exophthalmos, chemosis, and lid swelling of the ipsilateral ocular structures. The medical workup should include endoscopy, skull radiographs, orbital ultrasonography, and a cOlTIplete ophthalmic examination. Nuclear scintigraphy may be helpful in select cases and, eventually, computed axial tomography should be the greatest aid to diagnosis, prognosis, and treatment. At this time, most computed axial tomographic scan equipment can only handle small animals; it can be used in foals but is not widely available for adult horses. Ultrasound-guided biopsy may be possible in some cases. Although tUlTIOr removal via orbitotomy has been attempted in many cases, removal or treatment of orbital tumors usually requires enucleation and exenteration in the horse. Well-circumscribed orbital masses may be approached by orbitotomy, but the owners should also be cautioned that enucleation or exenteration may be necessary. Systemic hypotension was encountered in two of three horses having exenteration for orbital neuroendocrine tumors by Basher et a1. 3 This complication should be anticipated during orbital surgery, as neuroendocrine and other neural origin tumors frequently are included in the differential list for orbital neoplasia in horses. In addition, any extensive orbital surgery may occasionally stimulate the oculocardiac reflex, resulting in bradycardia and hypotension, which are potentially drastic complications for the anesthesiologi~t managing the anesthesia and recovery of an aged horse. The prognosis relnains guarded for all horses having orbital neoplasia. Early clinical suspicion coupled with an aggressive preoperative workup may somewhat improve the prognosis for select cases. Biopsy of the orbital mass and suspicious lymph nodes, chest radiographs, and other ancillary procedures may allow preoperative determination of prognosis when malignant tumors are suspected.

References 1. Angelos J, Oppenheim Y, Rebhun W, et al: Evaluation of breed as a risk factor for sarcoid and uveitis in horses. Anim Genet 19:417, 1988 2. Barnett KC, Platt H: Intraocular melanomata in the horse. Equine Vet J 10(suppl):76, 1990 3. Basher AW, Severin GA, Chavkin MJ, et al: Orbital neuroendocrine tumors in three horses. JAVMA 210:668, 1997 4. Bistner S, Can1pbell RJ, Shaw D, et al: N-euroepithelial tU1110r of the optic nerve in a horse. Cornell Vet 73:30, 1983 5. Bolton JR, Lees MJ, Robinson WF, et al: Ocular neoplasms of vascular origin in the horse. Equine Vet J 10(suppl):73, 1990 6. Brostrom H: Equine sarcoids. A clinical and epidemiological study in relation to equine leucocyte antigens (ELA). Acta Vet Scand 36:223, 1995 7. Bucher K, Szalai G, Marti E, et al: Tumour suppressor gene p53 in the horse: Identification, cloning, sequencing and a possible role in the pathogenesis of equine sarcoid. Res Vet Sci 6:114, 1996 8. Crawley GR, Bryan GM, Gogolewski RP: Ocular hemangioma in a horse. Equine Pract 9:11,1987

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Address repril1 t requests to William C. Rebhun, DVM Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, NY 14853