Diffuse Iris Melanoma Nicki Poppenger Dr. Lucien Vallone Dr. Eric Ledbetter Senior Seminar paper Cornell University College of Veterinary Medicine March 11, 2015 Keywords: feline, diffuse iris melanoma, iridal hyperpigmentation ABSTRACT Diffuse iris melanoma is uncommon, but is the most common primary intraocular neoplasia in cats.1,2 The diagnosis can be difficult to make, and determining an appropriate prognosis can be nearly impossible. Treatment options associated with this disease are quite limited, and the best care for these patients is achieved on a case-by-case basis. There is a need for further research and investigation to help assist us in the care of these patients. This case report will focus on the clinical presentation, diagnosis, treatment options, and prognosis of diffuse iris melanoma in an approximately 8-year-old, castrated male, domestic shorthair cat. CASE HISTORY An approximately 8-year-old castrated male domestic shorthair feline was presented to the Cornell University Hospital for Animals’ Ophthalmology service on 9/12/14 for a 3-year history of a slowly progressive area of hyperpigmentation on the iris OS. In addition to the hyperpigmentation, his owner perceived a sensitivity to light manifested as mild blepharospasm. He had been a stray found on the side of the road after being hit by a car, and subsequently had his left hind limb amputated. Following his recovery he was adopted by his current owners from the animal hospital that treated him. CLINICAL FINDINGS On physical exam the patient was bright, alert, and responsive. He had a good body condition score of 6/9 and weighed 4.7kg. His vital parameters were within normal limits and there were no overt signs of systemic illness. He was extremely good natured and cooperative. Upon ophthalmic exam he was found to have multi-focal to coalescing hyperpigmented, irregular areas over the iris OS. The pigmentation extended to the base of the irisouter edges of the iris, almost completely changing the color of the left eye from green to various shades of brown. Upon pupillary light reflex, anisocoria was observed with diminished pupillary constriction OS. Slit- lamp examination showed the topography of the iris as thicker, raised and irregular as well as hyperpigmented. he iris surface normally has a smooth, velvety appearance. It also revealed exfoliated cellular debris floating in the anterior chamber OS. The remainder of his ophthalmic exam was unremarkable with no other changes in the left eye, and no abnormalities in his right eye. PROBLEM LIST Our problem list included significant progression of unilateral hyperpigmentation over the iris OS, reduced function of the iridal muscles OS, and the presence of cellular debris within the anterior chamber OS. DIFFERENTIAL DIAGNOSIS Possible causes for the patient’s clinical signs include benign melanosis, also known as iris nevus, or “freckle”. This can be focal or diffuse, flat hyperpigmentation over the anterior surface of the iris. It can be the result of an increased amount of melanin in the melanocytes, or an increased number of melanocytes. Diffuse iris melanoma is the most common intraocular tumor in cats, and presents as diffuse pigmentation over the iris.1,2 Another possibility is a pPigmented uveal cyst, which is a pigmented sphere that is frequently attached at the pupillary margin. Iridal discoloration or hyperpigmentation may also be due to chronic inflammation. Diffuse iris melanoma quickly became the most likely, and presumptive diagnosis. The unilateral nature of our patient’s lesion is consistent with this disease, while benign melanosis frequently occurs bilaterally. The hyperpigmentation was thick, raised and irregular as seen with diffuse iris melanoma, rather than flat. The exfoliated cellular debris floating in the anterior chamber is indicative of an infiltrative process. Also, the diminished pupillary constriction demonstrated how the iridal muscles had been affected. Unfortunately, the only way to acquire a definitive diagnosis is through submission of the affected eye for histopathology following enucleation. Ideally we would like to confirm that there is in fact a malignant process occurring before this procedure, but this isn’t possible. Aqueocentesis is not recommended due to the potential for intraocular complications, such as hemorrhage, and the possibility of inducing metastasis through disruption of the blood-ocular barrier. Retrieval of cells on the surface of the iris or by aspiration of the surrounding aqueous humor has provided limited information on differentiating between benign and malignant lesions. DIAGNOSTICS It was decided that further diagnostics were warranted to help determine the appropriate treatment. We wanted to look for any signs of systemic illness and metastatic disease. The most common sites of metastasis are the lungs, liver, and regional lymph nodes.2 It has also been reported to metastasize to long bones in rare cases.3 A complete blood cell count (CBC), and chemistry panel were run to look at organ function. Three-view thoracic radiographs were taken to look for any masses already present in the lungs. An abdominal ultrasound was also performed to look for any signs for metastasis in the liver or elsewhere in the body. All tests concluded with no abnormal findings. We became hopeful that we had perhaps diagnosed the iris melanoma early enough in the disease process to warrant preventative measures, such as enucleation. TREATMENT OPTIONS There are many factors to take into consideration when determining the best treatment option for patients with diffuse iris melanoma. Diode laser ablation has been used for destruction of focal areas of melanocytes. This doesn’t prevent recurrence, however, and given that this disease in cats is multifocal in nature we would expect new lesions in the future. Theis most significant deterrence from this modality is the increased risk of metastasis through the break-down of the blood-ocular barrier that it causes. This treatment option is more appropriate and successful with use in dogs or other species. In dogs and other species diffuse iris melanoma occurs focally and is a benign process with littleno risk of metastasis. Another approach to treatment would be serial monitoring of the affected areas to assess growth and look for signs of infiltration to other parts of the eye. The tumor cells often spread to the iridocorneal angle, and can obstruct aqueous outflow eventually leading to increased ocular pressure and glaucoma. This would be a plausible conservative approach in patients with smaller areas of hyperpigmentation that were perhaps still being distinguished from a potentially benign process. Also, this approach would be appropriate in older cats that may succumb to another disease process before metastasis is likely to occur. Neither of these circumstances were applicable for our patient, however, as he was middle aged, and the affected areas were already visibly expansive with evidence of infiltration to the iridal muscles. This brings us to enucleation of the affected eye, which can be both curative and diagnostic. This approach has been shown to prolong survival time by decreasing the risk of metastasis if done early enough in the disease process. It seemed to be the best option for our patient given the significant progression of the disease and the likelihood that he would be dealing with secondary complications, such as glaucoma if not metastasis within his lifetime. The patient was discharged to his owner, while treatment options were considered. Shortly thereafter we were notified that the owners would be seeking enucleation of the eye through their primary care veterinarian. We strongly encouraged them to pursue a definitive diagnosis through submission of the eye for histopathology, which was done. HISTOPATHOLOGY The patient’s primary care veterinarian shared the histopathology results with us, which confirmed diffuse iris melanoma. It was a relief for the owners to hear that there was in fact reason to remove the eye, and our suspicion was correct that we were dealing with a malignant process. The histopathology report revealed that there were areas where the iris was thickened by dense infiltrates of mildly pleomorphic, heavily pigmented epitheliod cells and melanophages. There was also an area of the drainage angle with increased melanophages. Minimal mitotic activity was seen with only 1 per 10 high power fields. There was mild nuclear size variation in most cells with very few cells having moderate nuclear enlargement. And all cells had small nucleoli. Lack of invasion of the sclera was confirmed, and excision appeared to be complete. Histopathology findings associated with a grave prognosis in one report included a high mitotic index, full-thickness iris involvement, and the presence of tumor cells in the scleral venous plexus.3? Malignancy has also been associated with large round nucleus and prominent nucleoli. Since the patient lacked these characteristics, we have reason to believe his prognosis may not be poor. Comment by Caroline Manring: Hm… PROGNOSIS The prognosis of diffuse iris melanoma is fair to guarded at best. One report describes it as poor with a high risk of metastasis and a shortened life span.4? There is another report, which can associate a better prognosis with certain clinical or histological aspects in certain cases. Reasons to support a better prognosis in the patient included lack of invasion beyond the iris and iridocorneal angle. Also, lack of secondary complications within the eye, a low mitotic index, and enucleation early in the disease process were positive prognostic indicators. . DISCUSSION Diffuse iris melanoma is most commonly diagnosed in cats that are more than 9 years old, with no breed or sex predilection.1 It presents as progressive pigmentation of the iris, which can occur over months to several years.1 Over time, both the extent and amount of pigmentation generally increase. The condition is usually unilateral in nature, and is clinically characterized by malignant growth of melanocytes.4? Melanin within the melanocytes give the dark appearance to the cells. These tumors have presented as amelanotic melanomas as well.3? Iris melanomas arise on the anterior surface of the iris and eventually involve most of the iris making it thicker and less mobile causing diminished pupillary constriction as seen in our patient. It can then extend to the iridocorneal angle, ciliary body, scleral venous plexus, sclera, and choroid.5 Secondary complications within the eye due to the progression of the disease include glaucoma, and anterior uveitis and ruptured lens capsules in rare cases.6,7 It is regarded as a potentially aggressive malignant neoplasm with potential for metastatic disease that can have long latency periods.5? The most common sites of metastasis include the liver, lungs, and regional lymph nodes.1,2 There has been report of presence in long bones, and widespread metastasis as well in rare cases.3 Metastasis may not be noted until necropsy, but the rate may be as high as 63%.3? Enucleation of the affected eye is often the preferred course of action for both a definitive diagnosis and curative treatment. When enucleation is performed in the early stages of disease, while the tumor is confined to the iris stroma, affected cats can achieve average life spans.5? However, if invasion of the ciliary body stroma, or sclera is present before enucleation, there is a progressively poorer prognosis.5? The case is similar ifs glaucoma is present before enucleation as well. Perhaps the most challenging aspect of treating this disease in cats is deciding whether or not enucleation will benefit the patient. There is a lack of clinical hallmarks that correlate to the histological signs that signify the change from benign pigmentation to the development of a melanoma, or when there is infiltration beyond the iris. The diagnosis is often not made until there are already secondary changes to the eye from the malignant process. Predisposing factors are yet to be seen. A, and an appropriate treatment to stop the progression of the disease before enucleation is necessary is still unknown. Further information to better determine the possibility of or time line for metastasis is also needed, especially for cases in middle-aged cats. It can be particularly difficult to determine whether or not enucleation is necessary in this age group, since metastasis may not occur until late in the disease process, long after they have succumbed to another disease. Increases in the number and size of pigmented areas, changes in pupillary size or shape, and elevated intraocular pressure are all a good basis for justifying enucleation as the treatment of choice.3 Comment by Caroline Manring: Oops, pick one REFERENCES 1Pigatto J.A.T., Hünning P.S., Almeida A.C.V.R., Pereira F.Q., Freitas L.V.R.P., Gomes C., Omes C., Schiochet F., Rigon G.M. Igon G.M. & Driemeier. “Diffuse Iris Melanoma in a Cat.” Acta Scientiae Veterinariae. 38(4) (2010): 429-432 2Conceição, Luciano Fernandes da, Ribeiro, Alexandre Pinto, Piso, Dunia Yisela Trujillo, & Laus, José Luiz. “Considerations about ocular neoplasia of dogs and cats.” Ciência Rural, 40(10) (2010): 2235-2242 3Kirk N.Gelatt, Brian C. Gilger, Thomas J. Kern. “Diffuse Iridal Melanoma.” Veterinary Ophthalmology. Two Volume Set, 5th Edition (2013): 1511-1512 4Iuliana Ionascu, Georeta Dinescu, Cucos Cataline Anca. “Iris Melanoma in cats.” Veterinary Medicine Journal. 58(4): 80-87 5Bruce H. Grahn, Robert L. Peiffer, Cheryl L. Cullen and Deborah M. Haines. “Classification of feline intraocular neoplasms based on morphology, histochemical staining, and immunohistochemical labeling” Veterinary Opthalmology Volume 9 Issue 6 (2006): 395-403 6Jennifer B. Kalishman, Rick Chappell, Lisa A. Flood and Richard R Dubielzig. “A Matched Observational Study of Survival in Cats with enucleation due to diffuse iris melanoma.” Veterinary Ophthalmology 1(1) (1998): 25-29 7Brooks, Dennis E. "Glaucoma in the dog and cat." Veterinary Clinics of North America: Small Animal Practice. 20(3) (1990): 775-797 9