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Ocular Squamous Cell Carcinoma
C H A P T E R
149
Ocular Squamous Cell Carcinoma
ELIZABETH A. GIULIANO
T
umors affecting the orbit, eyelid, or globe often manifest initially as signs of ocular discomfort or mucopurulent discharge, but they can be identified before the development of serious ocular or periocular complications through careful ophthalmic examination. Squamous cell carcinoma (SCC) is the most common neoplasm of the equine eye and ocular adnexa and is the second most common tumor affecting the horse overall. Squamous cell carcinoma may involve any or all of the corneoconjunctiva, bulbar conjunctiva, third eyelid, and eyelids. The biologic behavior of SCC varies depending on location. Tumors are typically locally invasive and slow to metastasize. Metastasis to local lymph nodes, salivary glands, and thorax can occur. A poorer prognosis has been associated with SCC involving the eyelid, compared with SCC of the nictitating membrane, nasal canthus, or limbus. Several risk factors have been associated with development of SCC. Ultraviolet light exposure is believed to play an important role in the pathogenesis of SCC in horses and other species. Exposure to ultraviolet light can lead to mutations in the p53 gene, an important regulator of cell growth and proliferation, with resulting development of SCC. Additionally, a breed predilection exists for draft horses, Appaloosas, and American Paint Horses. Finally, a higher frequency of ocular SCC has been reported in horses lacking pigmentation around the eye, such as Pintos.
EXAMINATION AND DIAGNOSTIC PROCEDURES
Given the sometimes slow-growing nature of ocular SCC and the overall small area this tumor may occupy, compared with the total body surface area of a horse, this neoplasm is often not detected by the owner or general practitioner until it is advanced. For this reason, it is recommended that the equine practitioner perform a complete ophthalmic examination as part of any routine health check or prepurchase examination. When presented with any ophthalmic abnormality, preservation of vision and ocular comfort should guide the diagnostic and therapeutic plan. The horse should first be examined from a distance to facilitate assessment of facial symmetry and eyelash positioning. One of the first clinical signs observed with ocular pain in horses is ventral deviation of the eyelashes on the affected side. The regional lymph nodes and parotid salivary glands should be palpated. A room with controlled lighting is ideal for examination of the globe and periocular structures and should be used for any animal ophthalmic exam; however, access to adjustable lighting is not always possible in equine practice. A dark blanket placed over the examiner’s and horse’s heads helps create a darkened environment. The complete ophthalmic examination and derivation of a minimum ophthalmic database should be undertaken during all ophthalmic examinations with few exceptions. Components of
624
the minimum ophthalmic database include menace response, direct and consensual pupillary light reflex, palpebral reflex, Schirmer tear test, fluorescein stain, and tonometry (Box 149-1). Tonometry must be performed with caution in any horse with a deep corneal ulcer to avoid globe perforation. Retropulsion and assessment of ocular motility are often helpful in horses with suspected orbital tumors or intraocular tumors with extrascleral extension. Retropulsion also enables the practitioner to more thoroughly examine the third eyelid (nictitans), a common site for SCC in horses. To better determine prognosis and plan treatment, gentle digital palpation of the orbital rim is essential. This is best accomplished with the horse sedated. Using a gloved finger lubricated with a small volume of ophthalmic ointment, the examiner inserts the finger into the conjunctival fornix and palpates the entire orbital rim through the mucosa of the upper and lower fornices. When SCC has invaded local surrounding tissues, the orbital rim often cannot be felt in areas of neoplastic infiltration. After a complete ophthalmic examination has been performed, diagnostic imaging may be indicated, such as ocular ultrasound, skull radiographs, and computed tomography or magnetic resonance imaging. These modalities are especially helpful in horses with SCC in which evidence of bony extension is likely to alter the prognosis or surgical planning. Fine-needle aspiration of the regional lymph nodes, parotid salivary gland, or both should be performed when lymphadenopathy is detected or if there is local invasion of tumor. Definitive diagnosis of SCC should always be obtained on the basis of biopsy and histologic diagnosis. Consultation with or referral to a veterinary ophthalmologist may be helpful. Members of this specialty group can easily be located at www.acvo.org.
Clinical Features of Ocular and Periocular Squamous Cell Carcinoma Clinical features of SCC and its precursor lesions, which include actinic keratosis, epithelial dysplasia, chronic keratosis, and carcinoma in situ, are variable. Although SCC may arise from any location on the globe or periocular tissues, commonly affected sites include the temporal region of the limbus, leading edge of the nictitans, and eyelid margins. Classic features of this tumor type include pink to white, raised, friable, vascularized lesions with a cobblestone- or cauliflower-like appearance (Figures 149-1 to 149-4). Necrotic tumor surfaces with a white “cake frosting” appearance from secondary bacterial infection may impart a fetid odor to the lesion. Proliferative SCC arising from the eyelid and nictitans may be pedunculated with a broad base (see Figure 149-3). Ulcerated forms of this tumor typically cause erosion of the eyelid margins, medial canthus, or nictitans (see Figure 1494). Both proliferative and ulcerated forms of SCC may be
CHAPTER
BOX 149-1
Key Components of a Complete Ophthalmic Examination for Horses With Squamous Cell Carcinoma*
1. Menace response 2. Pupillary light reflex (direct and consensual) 3. Palpebral reflex 4. Schirmer tear test 5. Fluorescein stain 6. Tonometry (perform with caution in horses that have a deep corneal ulcer) 7. Careful examination of the anterior and posterior segments 8. Globe retropulsion and digital orbital palpation *The examination should be performed in the order listed during both a diagnostic examination and evaluations to assess response to treatment.
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present concurrently. If left untreated, local orbital invasion can ensue (Figure 149-5), resulting in substantial ocular discomfort and necessitating exenteration, which is removal of the orbital contents and eyelids. Differential diagnoses for SCC include papilloma, habronemiasis, eosinophilic conjunctivitis, foreign body granuloma, amelanotic melanoma, cutaneous mastocytoma, and other causes of blepharitis or keratoconjunctivitis. Although most SCCs have the described typical appearance at initial evaluation, definitive histologic diagnosis should always be obtained.
TREATMENT
Ocular and periocular tumors in horses represent a unique therapeutic challenge to equine practitioners as a consequence of both anatomic location and the unique characteristics of SCC. Reconstructive surgery to remove extensive masses affecting the globe or adnexa while maintaining cosmesis and vision is challenging and, at times, impossible. The eye is a delicate organ and is prone to visual compromise from secondary inflammation. Special instrumentation coupled with skill in microsurgical techniques is needed for removal of corneal or conjunctival masses with the best chance for a visual outcome. Eyelids act as the pri mary “windshield wiper” of the cornea, and, as such, any
Figure 149-1 Photograph of a 7-year-old Paint Horse gelding with temporal limbal and ventral nasal eyelid squamous cell carcinoma (SCC). The upper eyelid and temporal portion of the lower eyelid have crusted lesions that are consistent with actinic keratosis, which is often a precursor lesion to SCC. Figure 149-3 Photograph of a proliferative, pedunculated, cauliflowertype squamous cell carcinoma on the lower eyelid of a 10-year-old Paint Horse gelding.
Figure 149-2 Photograph of lower medial canthal squamous cell carcinoma in a 12-year-old Appaloosa mare. This tumor has a classic cobblestone- or cauliflower-like appearance.
Figure 149-4 Photograph of a 9-year-old Paint Horse mare with ulcerative squamous cell carcinoma involving the lower eyelid.
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irregularity in eyelid shape or contour can result in chronic keratitis, ulceration, and discomfort. Preservation of eyelid function must be balanced with the need for adequate tumor resection. Eyelid tumors in horses are often not amenable to complete excision. Eyelid reconstruction surgery, such as the H-plasty or bucket-handle procedures commonly performed in small animals, is nearly impossible in horses because of the tight adherence of periocular skin to underlying fascia and bone. Tumor characteristics also play a role in treatment outcome for SCC. Surgical excision alone for ocular or periocular SCC carries a high recurrence rate and often results in incomplete tumor resection if the mass is larger than 1 cm in diameter. For this reason, veterinary ophthalmologists rarely recommend sharp dissection alone. Various ancillary treatments have been reported, including cryosurgery, hyperthermia, chemotherapy, radiotherapy, immunotherapy, and
Figure 149-5 Photograph of the eye of a 14-year-old Tennessee Walking Horse mare with extensive eyelid squamous cell carcinoma and local invasion in the bony orbit.
laser ablation (Table 149-1). Reported success rates vary, and the published literature on ophthalmic SCC in horses includes many reports with low case numbers and poor longterm follow-up. Additionally, the extent of tumor involvement is not always well characterized, leading to publication of unrealistically positive outcomes in some studies that included cases with superficial tumors for which virtually any type of treatment may have yielded favorable results.
Surgical Tumor Removal The SCC treatment option selected depends on the location and extent of tumor, availability and cost of treatment, functional and cosmetic considerations, potential complications, and risks to both horse and owner. Prognosis for ophthalmic SCC is generally favorable for tumors smaller than 1 cm in diameter and for circumscribed tumors arising from the leading edge of the third eyelid, where the likelihood of obtaining clean surgical margins is greatest. When horses are euthanized because of SCC, it is rarely because of the effects of distant metastasis but rather because tumor has extensively infiltrated the orbit and adnexa, the horse is uncomfortable or blind from local disease, or the owner has financial constraints. Early diagnosis and prompt, appropriate treatment are the clinician’s best defense against ophthalmic SCC. Surgical debulking alone is rarely recommended, irrespective of tumor location. In most instances, general anesthesia yields the optimal controlled surgical environment for tumor resection and ancillary therapy. In cases of limbal SCC in which keratoconjunctivectomy is required, appropriate surgical instrumentation and magnification to facilitate complete tumor removal should be used. The reader is referred to additional sources for a more complete discussion of microsurgical instrumentation and techniques. For reasons already discussed, surgical removal of eyelid tumors must be performed judiciously because preservation of eyelid function is essential to corneal health and clarity. Lesions of SCC arising from the third eyelid often represent the easiest form
TABLE 149-1 Summary of Treatments Used in Horses With Ophthalmic Squamous Cell Carcinoma*
Treatments
Recurrence Rate (%)
Follow-Up (months)
Surgery alone
42-62
12-48
Surgery + cryotherapy
30-67
12-36
25
6-10
7-100 11-15 8-66
12 24-72 12-72
0 (1 case) 25 (4 cases)
18 12
Surgery + hyperthermia
Surgery + intratumoral chemotherapy Surgery + irradiation β-irradiation (90Sr) Interstitial radiotherapy (222Rn, 198Au, 192Ir, 60Co, 137Cs)
Surgery + immunotherapy (BCG) Surgery + CO2 laser ablation
References Mosunic et al (2004) King (1991) King (1991) Hilbert (1977) King (1991) Wilkie (1990) Grier (1980) Theon (1997, 1994, 1993) Theon (1994) Dugan (1991) King (1991) Wilkie (1990) Walker (1986) Frauenfelder (1982) Wyn-Jones (1979) Gillette (1964) McCalla (1992) English (1990)
*Because success rates and follow-up times vary among studies and the extent of tumor involvement is not always well characterized, some results may have been skewed by the inclusion of cases involving superficial tumors in which any treatment may have yielded equally favorable results. BCG, Bacillus Calmette-Guérin.
of this neoplasm to treat, especially if the mass is smaller than 1 to 2 cm in diameter. Horses do not appear to develop keratoconjunctivitis sicca as frequently as small animals do after complete removal of the third eyelid. Therefore complete removal of an affected third eyelid in a horse, including all of the cartilage so that chronic irritation of the medial canthus from exposed cartilage edges is avoided, often affords the best chance for attaining clean surgical margins in this affected area.
Ancillary Treatment Cryotherapy
Following surgical resection of SCC, various ancillary treatments can be used. One of the easiest, safest, and least expensive options is cryotherapy. In the author’s clinical equine ophthalmic practice, liquid nitrogen delivered through a Brymill cryogenic system is used. These systems are readily available through distributors that can be located by a routine Internet search. Regardless of the anatomic site affected, the author performs a double freeze-thaw over the wound bed. Faster freezes and slower thaws improve cryodestruction of residual tumor cells. When performing cryotherapy on the cornea, the clinician must be careful not to overfreeze, which can damage the corneal endothelium and result in persistent corneal edema. Additionally, a lubricated plastic spatula should be placed over the nonaffected portion of the cornea to protect healthy tissue. Some ophthalmologists advocate the use of temperature probes to ensure that core temperature reaches at least −30° C; however, this is impractical at certain sites, such as the cornea. A useful clinical parameter is to observe the ice ball formed, with the goal of completely covering the wound bed and extending 2 to 5 mm beyond the surgical margins. Tissue necrosis, sloughing, and depigmentation are adverse effects of this treatment modality. In the author’s experience, horses treated for corneoconjunctival SCC in this way appear surprisingly comfortable after surgery and require only routine management for a corneal ulcer. The latter includes administration of a broad-spectrum topical antimicrobial ointment three to four times daily for 7 to 10 days, mydriatic ointment before surgery and to effect for 3 to 4 days, and systemic nonsteroidal antiinflammatory drugs for 5 to 7 days. As with any mass removal, resected tissue should be submitted for histologic diagnosis if preoperative biopsy was not performed.
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disadvantages include risk for exposure of veterinary personnel to cisplatin, need for multiple (four to six) treatments over time, profound periocular or ocular inflammation, expense, and induction of photosensitization with some agents (topical 5-FU), necessitating restricted exposure to sunlight during the treatment interval. Because of increasingly stringent regulations regarding compounding of chemotherapeutic agents in many states, a licensed compounding pharmacist should be consulted for assistance with the legal aspects of compounding and subsequent intralesional administration when treating horses with SCC.
Radiation Therapy
β-Radiation delivered by strontium-90 has been used successfully for treatment of small, superficial tumors following keratoconjunctivectomy and in some horses with SCC involving the eyelid. Most commonly, a dose of 75 to 100 Gy per 1-cm site is used. β-Radiation does not penetrate tissues deeply, and its use is therefore limited to superficial small lesions. Seventy-five percent of β-rays are absorbed by the first 2 mm of tissue and much of the remainder by the next 1 mm. Interstitial radiotherapy is still available at some referral institutions for treatment of periocular SCC. Various isotopes, including cesium-173, radon-222, gold-198, and iridium-192, have been used. Administration of radioactive material is often impractical in horses because special facilities and licensure are required. In addition, radiotherapy can be costly, may result in clinically significant ophthalmic complications (e.g., keratitis and anterior uveitis, lid fibrosis, cataract formation, permanent hair loss, poliosis, blindness), and represents a potential hazard to personnel handling the horse.
Laser Therapy Carbon dioxide laser is currently used at some universities and specialty private practices for treatment of SCC in horses. The equipment is expensive, training is required to operate it, and the unit must be regularly serviced. Nevertheless, it has been used successfully to treat corneal SCC and some selected eyelid tumors as well.
Immunotherapy
Radiofrequency hyperthermia should be used to deliver temperatures of 50° C for 30 seconds. Treatment can be laborintensive, because six to eight treatment episodes 2 to 4 weeks apart may be required to effect a cure. Additionally, this treatment has attendant risks for causing ulcerative keratitis, stromal necrosis, and anterior uveitis, and it should be limited to use in tumors that are smaller than 5 mm in diameter because tissue penetration is limited.
Case reports describing the treatment of SCC with immunotherapy (bacille Calmette-Guérin) and systemic piroxicam (a cyclooxygenase-2–selective nonsteroidal antiinflammatory drug) have been published. Immunotherapy can be difficult to administer and time consuming, and it necessitates numerous injections that often cause necrosis and suppuration at the injection site. Because the number of published reports is limited and case-controlled studies have not been performed, definitive conclusions regarding the effectiveness of these treatment options for ophthalmic SCC in horses, compared with other treatments, cannot be made at present.
Intralesional Chemotherapy
Emerging Treatments
Intralesional chemotherapy has received mixed reviews as a treatment for periocular SCC. Cisplatin is an alkylating-like agent for which the mechanism of action is to bind DNA and inhibit replication of tumor cells. Mitomycin-C and bleomycin are antimicrobials with antitumor properties, and 5-fluorouracil (5-FU) is a pyrimidine antagonist that functions by inhibiting DNA synthesis. All these agents have been used, some anecdotally, to treat SCC in horses. The drugs have the advantage of being amenable to use in standing horses, but they also have certain disadvantages. The
A universally acceptable standard treatment for ocular and periocular SCC in the horse does not exist at this time. The ideal treatment would induce complete tumor regression, result in a long disease-free interval, preserve eyelid function, and result in good cosmesis. No single treatment modality for ocular and adnexal SCC in horses has proved to be 100% effective, and complications can threaten both visual outcome and long-term survival. Therefore a strong rationale exists for the development of new adjunctive treatments to enhance destruction of residual tumor cells
Radiofrequency Hypothermia
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beyond surgical margins. The author has been testing a new treatment modality for periocular SCC involving surgical resection and local photodynamic therapy.
Photodynamic Therapy Photodynamic therapy (PDT) is an evolving modality for treatment of various ocular ailments, including age-related macular degeneration, tumors, and atherosclerotic plaques. Photodynamic therapy involves administration of a combination of light and light-sensitive agents, such as porphyrin, a component of hemoglobin, in an oxygen-rich environment. Selective uptake and retention of a photosensitizer in a tumor, followed by irradiation with light of a particular wavelength, initiates tumor necrosis through formation of toxic singlet oxygen. The development of oxygen free radicals damages cellular organelles, DNA, and microvasculature of the treated tissue, resulting in inflammation and additional tissue destruction. Photodynamic therapy is a two-stage process. First, a photosensitizer is administered to the patient, typically by injection, and accumulates in rapidly proliferating cells. Illumination with an appropriate-wavelength laser light constitutes the second stage of therapy. Tumor selectivity is achieved through a combination of selective retention of the photoactive chemical by neoplastic cells and delivery of light to a specific area. Lasers are the primary energy source for activation of porphyrins in PDT because they emit light that is monochromatic (exactly one color), coherent (light waves are parallel, permitting precise focusing), and intense (allowing for shorter treatment times). Of particular importance in clinical veterinary applications is the advent of smaller, more affordable, diode lasers, which offer convenient mobility and affordability. Photodynamic therapy has several advantages over conventional therapy. Injection of a photosensitizer and localization of the agent in the tumor enables high tumor destruction activity while sparing healthy surrounding tissue and provides good to excellent cosmetic results. The newer generations of photosensitizers have shorter half-lives and are cleared from the circulation within 5 days in some instances; therefore this treatment can be used repeatedly without cumulative side effects. Local PDT for eyelid SCC in horses does not require that the horse be housed in isolation, as is necessary after radiation therapy. Additionally, there is no significant morbidity associated with treatment and no known drug interactions. The author has treated 23 horses with eyelid SCC to date with surgical resection and local PDT (Figure 149-6). Although follow-up is being closely monitored in treated horses, all but 2 horses have only required one treatment to effect an apparent cure. All horses in this case series have remained tumor free after treatment for a minimum of 1 year, and many for as long as 5 years. Preliminary results are highly favorable, suggesting that PDT may prove to be more effective, require fewer treatment episodes and shorter hospital stays, and result in good cosmesis with excellent preservation of eyelid function, compared with other treatment modalities available at present. The cost of some commercially available photodynamic agents remains high.
SUMMARY
The approach to management of SCC involving the eye is summarized (see Box 149-1). Completion of a thorough ophthalmic examination is the first step in the diagnosis of any ocular or periocular tumor. As with any neoplastic process, the earlier it is detected, the more likely it is that treatment
Figure 149-6 Photograph of the same horse as in Figure 149-2, 1 month after a single treatment with surgical debulking and local photodynamic therapy. The mucosa at the surgery site was well healed, and the horse had vision, was comfortable, and had no evidence of tumor regrowth.
will be effective and yield a successful outcome with regard to vision, ocular comfort, and overall systemic health of the horse. The practitioner plays a critical role in early diagnosis and management of SCC in horses. Understanding the risk factors associated with SCC (i.e., ultraviolet light exposure, breed predilection, and pigmentation patterns) will help guide the practitioner’s clinical rationale and diagnostic workup when presented with a mass lesion affecting the equine globe or adnexa. With careful examination, early SCC can frequently be detected on routine wellness examinations, before the owner is aware of an ophthalmic problem. Definitive diagnosis of SCC should be obtained by biopsy and histologic evaluation. Additional diagnostic tests, such as ultrasound, computed tomography, or magnetic resonance imaging, may be helpful in planning an optimal treatment strategy in difficult SCC cases. Surgical resection of ophthalmic SCC should be followed with ancillary therapy. After treatment has been initiated, regular recheck examinations to assess for recurrence of SCC in the original affected site and to screen for local metastasis are critical. Client education to ensure that SCC-affected horses receive as much protection as possible from ultraviolet light by means of eye masks, sunscreen application, and strategic turnout times represents another important aspect in management of this disease. Emerging new therapies such as PDT may improve disease-free intervals for horses with periocular SCC. Controlled prospective clinical trials are needed to evaluate the efficacies of various treatment methods for this important neoplasm.
Suggested Readings Dubielzig RR. Tumors of the eye. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press, 2002:739-754. Dugan SJ, Curtis CR, Roberts SM, et al. Epidemiologic study of ocular/adnexal squamous cell carcinoma in horses. J Am Vet Med Assoc 1991;198:251-256. Dugan SJ, Roberts SM, Curtis CR, et al. Prognostic factors and survival of horses with ocular/adnexal squamous cell carcinoma: 147 cases (1978-1988). J Am Vet Med Assoc. 1991;198:298-303.
Giuliano EA. Equine periocular neoplasia: current concepts in aetiopathogenesis and emerging treatment modalities. Equine Vet J 2010;37(Suppl):9-18. Giuliano EA, MacDonald I, McCaw DL, et al. Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses: a pilot study. Vet Ophthalmol 2008;11(Suppl 1):27-34. Giuliano EA, McCaw DL, MacDonald PJ, et al. Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses. Assoc Res Vision Ophthalmol Invest Ophthalmol Vis Sci 2004;45:E-3566. Giuliano EA, Ota J, Tucker SA. Photodynamic therapy: basic principles and potential uses for the veterinary ophthalmologist. Vet Ophthalmol 2007;10:337-343.
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MacDonald IJ, Dougherty TJ: Basic principles of photodynamic therapy. Porphyrins Phthalocyanines 2001;5:105–129. Mosunic CB, Moore PA, Carmichael KP, et al. Effects of treatment with and without adjuvant radiation therapy on recurrence of ocular and adnexal squamous cell carcinoma in horses: 157 cases (1985-2002). J Am Vet Med Assoc 2004;225: 1733–1738. Ota J, Giuliano EA, Cohn LA, et al. Local photodynamic therapy for equine squamous cell carcinoma: evaluation of a novel treatment method in a murine model. Vet J 2008;176:170-176. Theon AP, Pascoe JR. Iridium-192 interstitial brachytherapy for equine periocular tumours: treatment results and prognostic factors in 115 horses. Equine Vet J 1995;27:117-121.
149
Ocular Squamous Cell Carcinoma
ELIZABETH A. GIULIANO
T
umors affecting the orbit, eyelid, or globe often manifest initially as signs of ocular discomfort or mucopurulent discharge, but they can be identified before the development of serious ocular or periocular complications through careful ophthalmic examination. Squamous cell carcinoma (SCC) is the most common neoplasm of the equine eye and ocular adnexa and is the second most common tumor affecting the horse overall. Squamous cell carcinoma may involve any or all of the corneoconjunctiva, bulbar conjunctiva, third eyelid, and eyelids. The biologic behavior of SCC varies depending on location. Tumors are typically locally invasive and slow to metastasize. Metastasis to local lymph nodes, salivary glands, and thorax can occur. A poorer prognosis has been associated with SCC involving the eyelid, compared with SCC of the nictitating membrane, nasal canthus, or limbus. Several risk factors have been associated with development of SCC. Ultraviolet light exposure is believed to play an important role in the pathogenesis of SCC in horses and other species. Exposure to ultraviolet light can lead to mutations in the p53 gene, an important regulator of cell growth and proliferation, with resulting development of SCC. Additionally, a breed predilection exists for draft horses, Appaloosas, and American Paint Horses. Finally, a higher frequency of ocular SCC has been reported in horses lacking pigmentation around the eye, such as Pintos.
EXAMINATION AND DIAGNOSTIC PROCEDURES
Given the sometimes slow-growing nature of ocular SCC and the overall small area this tumor may occupy, compared with the total body surface area of a horse, this neoplasm is often not detected by the owner or general practitioner until it is advanced. For this reason, it is recommended that the equine practitioner perform a complete ophthalmic examination as part of any routine health check or prepurchase examination. When presented with any ophthalmic abnormality, preservation of vision and ocular comfort should guide the diagnostic and therapeutic plan. The horse should first be examined from a distance to facilitate assessment of facial symmetry and eyelash positioning. One of the first clinical signs observed with ocular pain in horses is ventral deviation of the eyelashes on the affected side. The regional lymph nodes and parotid salivary glands should be palpated. A room with controlled lighting is ideal for examination of the globe and periocular structures and should be used for any animal ophthalmic exam; however, access to adjustable lighting is not always possible in equine practice. A dark blanket placed over the examiner’s and horse’s heads helps create a darkened environment. The complete ophthalmic examination and derivation of a minimum ophthalmic database should be undertaken during all ophthalmic examinations with few exceptions. Components of
624
the minimum ophthalmic database include menace response, direct and consensual pupillary light reflex, palpebral reflex, Schirmer tear test, fluorescein stain, and tonometry (Box 149-1). Tonometry must be performed with caution in any horse with a deep corneal ulcer to avoid globe perforation. Retropulsion and assessment of ocular motility are often helpful in horses with suspected orbital tumors or intraocular tumors with extrascleral extension. Retropulsion also enables the practitioner to more thoroughly examine the third eyelid (nictitans), a common site for SCC in horses. To better determine prognosis and plan treatment, gentle digital palpation of the orbital rim is essential. This is best accomplished with the horse sedated. Using a gloved finger lubricated with a small volume of ophthalmic ointment, the examiner inserts the finger into the conjunctival fornix and palpates the entire orbital rim through the mucosa of the upper and lower fornices. When SCC has invaded local surrounding tissues, the orbital rim often cannot be felt in areas of neoplastic infiltration. After a complete ophthalmic examination has been performed, diagnostic imaging may be indicated, such as ocular ultrasound, skull radiographs, and computed tomography or magnetic resonance imaging. These modalities are especially helpful in horses with SCC in which evidence of bony extension is likely to alter the prognosis or surgical planning. Fine-needle aspiration of the regional lymph nodes, parotid salivary gland, or both should be performed when lymphadenopathy is detected or if there is local invasion of tumor. Definitive diagnosis of SCC should always be obtained on the basis of biopsy and histologic diagnosis. Consultation with or referral to a veterinary ophthalmologist may be helpful. Members of this specialty group can easily be located at www.acvo.org.
Clinical Features of Ocular and Periocular Squamous Cell Carcinoma Clinical features of SCC and its precursor lesions, which include actinic keratosis, epithelial dysplasia, chronic keratosis, and carcinoma in situ, are variable. Although SCC may arise from any location on the globe or periocular tissues, commonly affected sites include the temporal region of the limbus, leading edge of the nictitans, and eyelid margins. Classic features of this tumor type include pink to white, raised, friable, vascularized lesions with a cobblestone- or cauliflower-like appearance (Figures 149-1 to 149-4). Necrotic tumor surfaces with a white “cake frosting” appearance from secondary bacterial infection may impart a fetid odor to the lesion. Proliferative SCC arising from the eyelid and nictitans may be pedunculated with a broad base (see Figure 149-3). Ulcerated forms of this tumor typically cause erosion of the eyelid margins, medial canthus, or nictitans (see Figure 1494). Both proliferative and ulcerated forms of SCC may be
CHAPTER
BOX 149-1
Key Components of a Complete Ophthalmic Examination for Horses With Squamous Cell Carcinoma*
1. Menace response 2. Pupillary light reflex (direct and consensual) 3. Palpebral reflex 4. Schirmer tear test 5. Fluorescein stain 6. Tonometry (perform with caution in horses that have a deep corneal ulcer) 7. Careful examination of the anterior and posterior segments 8. Globe retropulsion and digital orbital palpation *The examination should be performed in the order listed during both a diagnostic examination and evaluations to assess response to treatment.
149 Ocular Squamous Cell Carcinoma
625
present concurrently. If left untreated, local orbital invasion can ensue (Figure 149-5), resulting in substantial ocular discomfort and necessitating exenteration, which is removal of the orbital contents and eyelids. Differential diagnoses for SCC include papilloma, habronemiasis, eosinophilic conjunctivitis, foreign body granuloma, amelanotic melanoma, cutaneous mastocytoma, and other causes of blepharitis or keratoconjunctivitis. Although most SCCs have the described typical appearance at initial evaluation, definitive histologic diagnosis should always be obtained.
TREATMENT
Ocular and periocular tumors in horses represent a unique therapeutic challenge to equine practitioners as a consequence of both anatomic location and the unique characteristics of SCC. Reconstructive surgery to remove extensive masses affecting the globe or adnexa while maintaining cosmesis and vision is challenging and, at times, impossible. The eye is a delicate organ and is prone to visual compromise from secondary inflammation. Special instrumentation coupled with skill in microsurgical techniques is needed for removal of corneal or conjunctival masses with the best chance for a visual outcome. Eyelids act as the pri mary “windshield wiper” of the cornea, and, as such, any
Figure 149-1 Photograph of a 7-year-old Paint Horse gelding with temporal limbal and ventral nasal eyelid squamous cell carcinoma (SCC). The upper eyelid and temporal portion of the lower eyelid have crusted lesions that are consistent with actinic keratosis, which is often a precursor lesion to SCC. Figure 149-3 Photograph of a proliferative, pedunculated, cauliflowertype squamous cell carcinoma on the lower eyelid of a 10-year-old Paint Horse gelding.
Figure 149-2 Photograph of lower medial canthal squamous cell carcinoma in a 12-year-old Appaloosa mare. This tumor has a classic cobblestone- or cauliflower-like appearance.
Figure 149-4 Photograph of a 9-year-old Paint Horse mare with ulcerative squamous cell carcinoma involving the lower eyelid.
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irregularity in eyelid shape or contour can result in chronic keratitis, ulceration, and discomfort. Preservation of eyelid function must be balanced with the need for adequate tumor resection. Eyelid tumors in horses are often not amenable to complete excision. Eyelid reconstruction surgery, such as the H-plasty or bucket-handle procedures commonly performed in small animals, is nearly impossible in horses because of the tight adherence of periocular skin to underlying fascia and bone. Tumor characteristics also play a role in treatment outcome for SCC. Surgical excision alone for ocular or periocular SCC carries a high recurrence rate and often results in incomplete tumor resection if the mass is larger than 1 cm in diameter. For this reason, veterinary ophthalmologists rarely recommend sharp dissection alone. Various ancillary treatments have been reported, including cryosurgery, hyperthermia, chemotherapy, radiotherapy, immunotherapy, and
Figure 149-5 Photograph of the eye of a 14-year-old Tennessee Walking Horse mare with extensive eyelid squamous cell carcinoma and local invasion in the bony orbit.
laser ablation (Table 149-1). Reported success rates vary, and the published literature on ophthalmic SCC in horses includes many reports with low case numbers and poor longterm follow-up. Additionally, the extent of tumor involvement is not always well characterized, leading to publication of unrealistically positive outcomes in some studies that included cases with superficial tumors for which virtually any type of treatment may have yielded favorable results.
Surgical Tumor Removal The SCC treatment option selected depends on the location and extent of tumor, availability and cost of treatment, functional and cosmetic considerations, potential complications, and risks to both horse and owner. Prognosis for ophthalmic SCC is generally favorable for tumors smaller than 1 cm in diameter and for circumscribed tumors arising from the leading edge of the third eyelid, where the likelihood of obtaining clean surgical margins is greatest. When horses are euthanized because of SCC, it is rarely because of the effects of distant metastasis but rather because tumor has extensively infiltrated the orbit and adnexa, the horse is uncomfortable or blind from local disease, or the owner has financial constraints. Early diagnosis and prompt, appropriate treatment are the clinician’s best defense against ophthalmic SCC. Surgical debulking alone is rarely recommended, irrespective of tumor location. In most instances, general anesthesia yields the optimal controlled surgical environment for tumor resection and ancillary therapy. In cases of limbal SCC in which keratoconjunctivectomy is required, appropriate surgical instrumentation and magnification to facilitate complete tumor removal should be used. The reader is referred to additional sources for a more complete discussion of microsurgical instrumentation and techniques. For reasons already discussed, surgical removal of eyelid tumors must be performed judiciously because preservation of eyelid function is essential to corneal health and clarity. Lesions of SCC arising from the third eyelid often represent the easiest form
TABLE 149-1 Summary of Treatments Used in Horses With Ophthalmic Squamous Cell Carcinoma*
Treatments
Recurrence Rate (%)
Follow-Up (months)
Surgery alone
42-62
12-48
Surgery + cryotherapy
30-67
12-36
25
6-10
7-100 11-15 8-66
12 24-72 12-72
0 (1 case) 25 (4 cases)
18 12
Surgery + hyperthermia
Surgery + intratumoral chemotherapy Surgery + irradiation β-irradiation (90Sr) Interstitial radiotherapy (222Rn, 198Au, 192Ir, 60Co, 137Cs)
Surgery + immunotherapy (BCG) Surgery + CO2 laser ablation
References Mosunic et al (2004) King (1991) King (1991) Hilbert (1977) King (1991) Wilkie (1990) Grier (1980) Theon (1997, 1994, 1993) Theon (1994) Dugan (1991) King (1991) Wilkie (1990) Walker (1986) Frauenfelder (1982) Wyn-Jones (1979) Gillette (1964) McCalla (1992) English (1990)
*Because success rates and follow-up times vary among studies and the extent of tumor involvement is not always well characterized, some results may have been skewed by the inclusion of cases involving superficial tumors in which any treatment may have yielded equally favorable results. BCG, Bacillus Calmette-Guérin.
of this neoplasm to treat, especially if the mass is smaller than 1 to 2 cm in diameter. Horses do not appear to develop keratoconjunctivitis sicca as frequently as small animals do after complete removal of the third eyelid. Therefore complete removal of an affected third eyelid in a horse, including all of the cartilage so that chronic irritation of the medial canthus from exposed cartilage edges is avoided, often affords the best chance for attaining clean surgical margins in this affected area.
Ancillary Treatment Cryotherapy
Following surgical resection of SCC, various ancillary treatments can be used. One of the easiest, safest, and least expensive options is cryotherapy. In the author’s clinical equine ophthalmic practice, liquid nitrogen delivered through a Brymill cryogenic system is used. These systems are readily available through distributors that can be located by a routine Internet search. Regardless of the anatomic site affected, the author performs a double freeze-thaw over the wound bed. Faster freezes and slower thaws improve cryodestruction of residual tumor cells. When performing cryotherapy on the cornea, the clinician must be careful not to overfreeze, which can damage the corneal endothelium and result in persistent corneal edema. Additionally, a lubricated plastic spatula should be placed over the nonaffected portion of the cornea to protect healthy tissue. Some ophthalmologists advocate the use of temperature probes to ensure that core temperature reaches at least −30° C; however, this is impractical at certain sites, such as the cornea. A useful clinical parameter is to observe the ice ball formed, with the goal of completely covering the wound bed and extending 2 to 5 mm beyond the surgical margins. Tissue necrosis, sloughing, and depigmentation are adverse effects of this treatment modality. In the author’s experience, horses treated for corneoconjunctival SCC in this way appear surprisingly comfortable after surgery and require only routine management for a corneal ulcer. The latter includes administration of a broad-spectrum topical antimicrobial ointment three to four times daily for 7 to 10 days, mydriatic ointment before surgery and to effect for 3 to 4 days, and systemic nonsteroidal antiinflammatory drugs for 5 to 7 days. As with any mass removal, resected tissue should be submitted for histologic diagnosis if preoperative biopsy was not performed.
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disadvantages include risk for exposure of veterinary personnel to cisplatin, need for multiple (four to six) treatments over time, profound periocular or ocular inflammation, expense, and induction of photosensitization with some agents (topical 5-FU), necessitating restricted exposure to sunlight during the treatment interval. Because of increasingly stringent regulations regarding compounding of chemotherapeutic agents in many states, a licensed compounding pharmacist should be consulted for assistance with the legal aspects of compounding and subsequent intralesional administration when treating horses with SCC.
Radiation Therapy
β-Radiation delivered by strontium-90 has been used successfully for treatment of small, superficial tumors following keratoconjunctivectomy and in some horses with SCC involving the eyelid. Most commonly, a dose of 75 to 100 Gy per 1-cm site is used. β-Radiation does not penetrate tissues deeply, and its use is therefore limited to superficial small lesions. Seventy-five percent of β-rays are absorbed by the first 2 mm of tissue and much of the remainder by the next 1 mm. Interstitial radiotherapy is still available at some referral institutions for treatment of periocular SCC. Various isotopes, including cesium-173, radon-222, gold-198, and iridium-192, have been used. Administration of radioactive material is often impractical in horses because special facilities and licensure are required. In addition, radiotherapy can be costly, may result in clinically significant ophthalmic complications (e.g., keratitis and anterior uveitis, lid fibrosis, cataract formation, permanent hair loss, poliosis, blindness), and represents a potential hazard to personnel handling the horse.
Laser Therapy Carbon dioxide laser is currently used at some universities and specialty private practices for treatment of SCC in horses. The equipment is expensive, training is required to operate it, and the unit must be regularly serviced. Nevertheless, it has been used successfully to treat corneal SCC and some selected eyelid tumors as well.
Immunotherapy
Radiofrequency hyperthermia should be used to deliver temperatures of 50° C for 30 seconds. Treatment can be laborintensive, because six to eight treatment episodes 2 to 4 weeks apart may be required to effect a cure. Additionally, this treatment has attendant risks for causing ulcerative keratitis, stromal necrosis, and anterior uveitis, and it should be limited to use in tumors that are smaller than 5 mm in diameter because tissue penetration is limited.
Case reports describing the treatment of SCC with immunotherapy (bacille Calmette-Guérin) and systemic piroxicam (a cyclooxygenase-2–selective nonsteroidal antiinflammatory drug) have been published. Immunotherapy can be difficult to administer and time consuming, and it necessitates numerous injections that often cause necrosis and suppuration at the injection site. Because the number of published reports is limited and case-controlled studies have not been performed, definitive conclusions regarding the effectiveness of these treatment options for ophthalmic SCC in horses, compared with other treatments, cannot be made at present.
Intralesional Chemotherapy
Emerging Treatments
Intralesional chemotherapy has received mixed reviews as a treatment for periocular SCC. Cisplatin is an alkylating-like agent for which the mechanism of action is to bind DNA and inhibit replication of tumor cells. Mitomycin-C and bleomycin are antimicrobials with antitumor properties, and 5-fluorouracil (5-FU) is a pyrimidine antagonist that functions by inhibiting DNA synthesis. All these agents have been used, some anecdotally, to treat SCC in horses. The drugs have the advantage of being amenable to use in standing horses, but they also have certain disadvantages. The
A universally acceptable standard treatment for ocular and periocular SCC in the horse does not exist at this time. The ideal treatment would induce complete tumor regression, result in a long disease-free interval, preserve eyelid function, and result in good cosmesis. No single treatment modality for ocular and adnexal SCC in horses has proved to be 100% effective, and complications can threaten both visual outcome and long-term survival. Therefore a strong rationale exists for the development of new adjunctive treatments to enhance destruction of residual tumor cells
Radiofrequency Hypothermia
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beyond surgical margins. The author has been testing a new treatment modality for periocular SCC involving surgical resection and local photodynamic therapy.
Photodynamic Therapy Photodynamic therapy (PDT) is an evolving modality for treatment of various ocular ailments, including age-related macular degeneration, tumors, and atherosclerotic plaques. Photodynamic therapy involves administration of a combination of light and light-sensitive agents, such as porphyrin, a component of hemoglobin, in an oxygen-rich environment. Selective uptake and retention of a photosensitizer in a tumor, followed by irradiation with light of a particular wavelength, initiates tumor necrosis through formation of toxic singlet oxygen. The development of oxygen free radicals damages cellular organelles, DNA, and microvasculature of the treated tissue, resulting in inflammation and additional tissue destruction. Photodynamic therapy is a two-stage process. First, a photosensitizer is administered to the patient, typically by injection, and accumulates in rapidly proliferating cells. Illumination with an appropriate-wavelength laser light constitutes the second stage of therapy. Tumor selectivity is achieved through a combination of selective retention of the photoactive chemical by neoplastic cells and delivery of light to a specific area. Lasers are the primary energy source for activation of porphyrins in PDT because they emit light that is monochromatic (exactly one color), coherent (light waves are parallel, permitting precise focusing), and intense (allowing for shorter treatment times). Of particular importance in clinical veterinary applications is the advent of smaller, more affordable, diode lasers, which offer convenient mobility and affordability. Photodynamic therapy has several advantages over conventional therapy. Injection of a photosensitizer and localization of the agent in the tumor enables high tumor destruction activity while sparing healthy surrounding tissue and provides good to excellent cosmetic results. The newer generations of photosensitizers have shorter half-lives and are cleared from the circulation within 5 days in some instances; therefore this treatment can be used repeatedly without cumulative side effects. Local PDT for eyelid SCC in horses does not require that the horse be housed in isolation, as is necessary after radiation therapy. Additionally, there is no significant morbidity associated with treatment and no known drug interactions. The author has treated 23 horses with eyelid SCC to date with surgical resection and local PDT (Figure 149-6). Although follow-up is being closely monitored in treated horses, all but 2 horses have only required one treatment to effect an apparent cure. All horses in this case series have remained tumor free after treatment for a minimum of 1 year, and many for as long as 5 years. Preliminary results are highly favorable, suggesting that PDT may prove to be more effective, require fewer treatment episodes and shorter hospital stays, and result in good cosmesis with excellent preservation of eyelid function, compared with other treatment modalities available at present. The cost of some commercially available photodynamic agents remains high.
SUMMARY
The approach to management of SCC involving the eye is summarized (see Box 149-1). Completion of a thorough ophthalmic examination is the first step in the diagnosis of any ocular or periocular tumor. As with any neoplastic process, the earlier it is detected, the more likely it is that treatment
Figure 149-6 Photograph of the same horse as in Figure 149-2, 1 month after a single treatment with surgical debulking and local photodynamic therapy. The mucosa at the surgery site was well healed, and the horse had vision, was comfortable, and had no evidence of tumor regrowth.
will be effective and yield a successful outcome with regard to vision, ocular comfort, and overall systemic health of the horse. The practitioner plays a critical role in early diagnosis and management of SCC in horses. Understanding the risk factors associated with SCC (i.e., ultraviolet light exposure, breed predilection, and pigmentation patterns) will help guide the practitioner’s clinical rationale and diagnostic workup when presented with a mass lesion affecting the equine globe or adnexa. With careful examination, early SCC can frequently be detected on routine wellness examinations, before the owner is aware of an ophthalmic problem. Definitive diagnosis of SCC should be obtained by biopsy and histologic evaluation. Additional diagnostic tests, such as ultrasound, computed tomography, or magnetic resonance imaging, may be helpful in planning an optimal treatment strategy in difficult SCC cases. Surgical resection of ophthalmic SCC should be followed with ancillary therapy. After treatment has been initiated, regular recheck examinations to assess for recurrence of SCC in the original affected site and to screen for local metastasis are critical. Client education to ensure that SCC-affected horses receive as much protection as possible from ultraviolet light by means of eye masks, sunscreen application, and strategic turnout times represents another important aspect in management of this disease. Emerging new therapies such as PDT may improve disease-free intervals for horses with periocular SCC. Controlled prospective clinical trials are needed to evaluate the efficacies of various treatment methods for this important neoplasm.
Suggested Readings Dubielzig RR. Tumors of the eye. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press, 2002:739-754. Dugan SJ, Curtis CR, Roberts SM, et al. Epidemiologic study of ocular/adnexal squamous cell carcinoma in horses. J Am Vet Med Assoc 1991;198:251-256. Dugan SJ, Roberts SM, Curtis CR, et al. Prognostic factors and survival of horses with ocular/adnexal squamous cell carcinoma: 147 cases (1978-1988). J Am Vet Med Assoc. 1991;198:298-303.
Giuliano EA. Equine periocular neoplasia: current concepts in aetiopathogenesis and emerging treatment modalities. Equine Vet J 2010;37(Suppl):9-18. Giuliano EA, MacDonald I, McCaw DL, et al. Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses: a pilot study. Vet Ophthalmol 2008;11(Suppl 1):27-34. Giuliano EA, McCaw DL, MacDonald PJ, et al. Photodynamic therapy for the treatment of periocular squamous cell carcinoma in horses. Assoc Res Vision Ophthalmol Invest Ophthalmol Vis Sci 2004;45:E-3566. Giuliano EA, Ota J, Tucker SA. Photodynamic therapy: basic principles and potential uses for the veterinary ophthalmologist. Vet Ophthalmol 2007;10:337-343.
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MacDonald IJ, Dougherty TJ: Basic principles of photodynamic therapy. Porphyrins Phthalocyanines 2001;5:105–129. Mosunic CB, Moore PA, Carmichael KP, et al. Effects of treatment with and without adjuvant radiation therapy on recurrence of ocular and adnexal squamous cell carcinoma in horses: 157 cases (1985-2002). J Am Vet Med Assoc 2004;225: 1733–1738. Ota J, Giuliano EA, Cohn LA, et al. Local photodynamic therapy for equine squamous cell carcinoma: evaluation of a novel treatment method in a murine model. Vet J 2008;176:170-176. Theon AP, Pascoe JR. Iridium-192 interstitial brachytherapy for equine periocular tumours: treatment results and prognostic factors in 115 horses. Equine Vet J 1995;27:117-121.