Robert L. Peiffer, Jr., DVM, PhD, DACVO
Emeritus Professor of Ophthalmology and Pathology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA; Senior Investigator, Merck Research Laboratories, West Point, PA, USA ; Adjunct Professor, William C. Frayer Ophthalmic Pathology Laboratory, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; Director, Bucks County Animal Ophthalmology, Doylestown, PA, USA
Ocular neoplasia arising from melanocytic cells offers both fascinating similarities and contrasts when comparing humans, dogs, and cats. In all three species melanocytic tumors are the most common primary intraocular neoplasm. In humans, uveal melanomas most commonly arise from the choroid and demonstrate spindle and epithelioid morphologic variants that allow for reasonable predictability of biologic behavior. While cats share with humans a significant risk for metastatic disease and tumor-related mortality, the most common clinical syndrome involves diffuse transformation of melanocytes on the anterior iris surface with a prolonged pre-malignant phase. In dogs, the majority of tumors arise from the anterior uvea and are benign, with marked similarities to human melanocytomas.
While the ophthalmologist must deal with melanocytic neoplasia arising in eyelid, orbit, and conjunctiva, the discussion that follows will be limited to melanocytic neoplasia arising from the globe itself in these species.
Neural crest cells are derived from ectoderm located at the margin of the neural plate. The cells of the cranial neural crest migrate into adjacent primary mesenchyme to give rise to secondary mesenchyme that in turn differentiates into the corneal stroma and uveal tissue, including the uveal melanocytes, as well as other ocular tissues. A subpopulation of neural crest cells will differentiate into dendritic melanocytes, characterized by tyrosinase activity, melanin granules, and a dendritic morphology.
The retinal, ciliary, and iridal epithelium, while likewise melanogenic, arises from the neuroepithelium of the optic cup; these tissues can give rise to neoplasia that must be differentiated from melanomas of melanocytic origin.
Melanocytic tumors may arise from cells that have not obtained a mature morphology; the most common morphologic variants are spindle cells and large, pigment-laden polyhedral-to round cells that if pigment-laden are referred to as melanocytoma cells. These tumors are termed nevi (singular-nevus, meaning spot) and are by definition benign, although nevus cells may undergo, albeit rarely, malignant transformation to melanoma. The majority of ocular melanomas arise de novo and are characterized by a range of morphology and biologic behavior. Benign hyperplasia of dendritic melanocytes is referred to as a freckle and has no malignant potential.
Melanocytic cells may produce variable amounts of melanin, correlating with a clinical spectrum of lesions that range from amelanotic to golden brown to black. Melanocytic cells require distinction from embryonic melanoblasts which possess melanocytic potential; melanophages which have ingested melanin produced elsewhere; and incidentally pigmented cells, typically epithelial, which acquire melanin granules produced by adjacent melanocytes.
Ocular melanocytosis, also referred to as melanosis oculi, is a unilateral congenital condition characterized by hyperpigmentation of the episclera and uveal tract due to the presence of increased numbers of plump melanocytes. If the periocular skin is involved, the condition is called oculodermal melanocytosis. While the lesion is considered benign, affected individuals have an increased risk of developing malignant melanomas.
Nevi are acquired lesions that may occur in the iris in up to 50% of the population: incidence in ciliary body is approximately 2%, in choroid 6%. Similar to other melanocytic tumors of the uvea, nevi show a predilection for lightly pigmented individuals (Caucasians) with blue irides and appear during puberty or young adulthood. Histologically the majority are composed of spindle cells, less commonly melanocytoma, epithelioid (composed of round or ovoid cells), and balloon cell variants. The lesions may remain stable over time, enlarge slowly or, very rarely, undergo malignant transformation.
Melanocytoma is an intraocular neoplasm with distinct clinical and histopathologic features. While first described as a heavily pigmented lesion involving the optic nerve head most commonly encountered in pigmented races (in contrast to uveal melanomas where the converse is true) and composed of large polyhedral cells with pigment laden cytoplasm and bland, small, round nuclei, similar tumors have been recognized in extrapapillary locations throughout the uveal tract. Malignant potential is similar to that of other nevi.
Bilateral diffuse uveal melanocytic proliferation is a paraneoplastic syndrome that occurs in patients with systemic carcinoma, and presents with a reticular funduscopic appearance related to diffuse, multinodular proliferation of nevoid cells within the choroid.
Uveal malignant melanoma occurs in the Caucasian population at a rate of approximately 1/200,000. Iris malignant melanomas represent 3-10% of human uveal melanomas and may be nodular or diffuse; secondary glaucoma may complicate the latter. Average age of diagnosis is during the 4th decade and prognosis, dependent on cell type, is generally favorable. Ciliary body and choroidal melanomas may likewise demonstrate nodular or diffuse growth patterns, the latter tending to be more aggressive. Cellular morphology, tumor size, vascular patterns, and growth rate are reliable prognosticators of potential for metastatic disease. The modified Callender classification categorizes tumors as spindle, mixed spindle and epithelioid, or epithelioid, with respective 5-year survival rates of 85%, 58% and 57%, although metastatic disease may not manifest until 5-15 years following diagnosis. Treatment options include enucleation, plaque radiotherapy, local resection, and other eye-sparing therapies; at this time available data does not adequately address management controversies.
Cat irides demonstrate both freckles and nevi that, while clinically may be challenging to distinguish, behave as one would predict--as static or slowly evolving solitary or multiple pigmented lesions. Nevi may enlarge to appear elevated. An interesting bilateral variant presents as concentric circumferential zones of iridal hyperpigmentation. Uveal malignant melanomas most commonly arise de novo in middle-aged or older cats as a diffuse or coalescing multifocal proliferation of angulated melanocytic cells on the iris surface; these cells are non-cohesive and readily exfoliate into the anterior chamber. After what may be a prolonged pre-malignant phase, the morphology assumes typical features of malignancy and the iris stroma is invaded in an anterior-to-posterior fashion. Morphology is variable with spindle, epithelioid, pleomorphic, and balloon cells encountered, without apparent relationship to prognosis; however full-thickness iris involvement and mitotic index may be of value in predicting behavior. As the ciliary cleft is invaded secondary glaucoma is a common complication; malignant cells egress the eye via the trabecular veins and the presence of tumor emboli in the scleral venous plexus is an ominous prognosticator. Tumor growth is usually slow but relentless and the tumor will eventually fill the eye and extend through the sclera, frequently along the emissaria.
As in humans, overt metastatic disease may not manifest for up to several years. Mortality rates are somewhat controversial but in neglected cases may approach 30-50%.
Nodular anterior and posterior uveal melanomas occur, but infrequently, and data is lacking to reach any conclusions on the metastatic potential of these lesions.
Management of small, localized lesions or lesions of uncertain includes observation at regular intervals (I recommend one month initially, then 3-4 months between examinations thereafter until behavior is ascertained). Early enucleation of eyes with progressive unilateral diffuse iris hyperpigmentation or rapidly growing nodular-pigmented lesions can be lifesaving. Early exfoliation of premalignant or malignant cells into the aqueous humor and subsequent entrapment in the trabecular meshwork beyond the reach of laser or scalpel makes less aggressive options, in the opinion of this ophthalmologist, a disservice to one's patient. Iridectomy or laser ablation should be reserved for slowly growing isolated pigmented iridal lesions of uncertain classification (which are somewhat predictably benign to begin with).
Limbal melanocytomas occur in cats, arising from the limbal melanocytes and most commonly seen in the superior quadrants. They tend to be slower growing than their canine counterparts and likewise are differentiated from extraocular extension of an anterior uveal malignant melanoma by careful ophthalmic examination, including gonioscopy. Treatment may be observation, or in expanding lesions surgical excision with or without grafting (as required by depth and extent of excision) or laser or cryoablation.
Freckles and nevi are relatively common in the canine iris; spindle cell iris nevi have been reported in puppies less than one year of age.
Anterior uveal melanomas occur more commonly than choroidal melanomas in dogs; behavior and morphology are independent of location. While occasionally encountered in young animals, they tend to be a disease of middle and old age. Approximately 90% are benign and consist of spindle and pigment-laden polyhedral cells very similar to those described in human melanocytomas and identical to the cells seen in canine and feline limbal melanocytomas. An uncommon morphologic variant, probably benign, is composed of small epithelioid cells with bland nuclear features. Malignant uveal melanomas tend to be spindle in morphology with cellular features typical of malignant cells; mitotic index provides a crude estimation of metastatic potential. Metastatic disease occurs in approximately 50% of dogs histologically confirmed malignant melanoma, for an overall mortality of uveal melanocytic neoplasia of about 5%. Both fulminant (within weeks) and delayed metastatic disease has been documented.
These tumors behave as one would expect, with more aggressive neoplasia growing rapidly, benign lesions expanding slowly. However, even benign melanocytomas can destroy globes, related to tumor-necrosis driven uveitis, intraocular hemorrhage (most commonly associated with iris neovascularization or rubeosis irides), and glaucoma related to iris neovascularization or tumor compromise of the outflow pathway are almost inevitable sequelae, sooner or later.
As with cats, observation to gain a sense of biologic behavior of small localized lesions is seldom if ever disadvantageous. Excision or laser ablation of such lesions may be considered but data is lacking as to the efficacy of these procedures in saving eyes and lives. Complicated eyes harboring melanomas (or suspected melanomas) are best enucleated, as are globes with rapidly growing pigmented lesions; surgery should be preceded of course by a thorough metastatic work-up, including chest radiographs and if available abdominal imaging. In elderly or one-eyed dogs with slow-growing lesions I counsel periodic observation as a reasonable management option.
Limbal melanocytomas occur in dogs of all ages and breeds with a predisposition for Alsatians and Labrador Retrievers. They occur most commonly in the superior quadrants; growth rate is variable. They are benign lesions and rarely extend intraocularly to jeopardize comfort and vision. A leading margin of lipid degeneration of the cornea is a common association. Gonioscopy will exclude the possibility of an anterior uveal melanocytic neoplasm with trans-scleral extension. Therapeutic options should be individualized based upon size and growth rate and include those modalities listed above for the cat.
Ocular melanocytosis is a bilateral (although not always symmetrical) disease encountered in elderly terriers and occasionally other breeds related to an insidious pan-uveal proliferation of large, non-cohesive pigment laden cells similar to those seen in melanocytoma. The irides are hyperpigmented, and the melanocytoma cells can be seen circulating with the aqueous and adherent to the anterior lens capsule with the aid of the biomicroscope. Intrascleral extension imparts a grey discoloration to the intercalary sclera. As the ciliary cleft is occluded by melanocytoma cells a refractory glaucoma develops and visual prognosis is unfortunately poor. As morphology would imply the disease is benign in terms of metastatic potential.
In all three species our diagnostic acumen of melanocytic ocular neoplasia is expanding as imaging technologies extend the limitations of routine ophthalmic examination and the science of fine needle aspiration of these lesions is explored. Therapeutic modalities other than enucleation being studied in humans may or may not have advantages and applicability to these lesions in dogs and cats. The cornerstone of management will remain a suspicion for and knowledge of the behavior of these lesions and selecting a course offering optimal benefit to the patient.
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21. Peiffer, RL, Simons KB (eds): Ocular Tumors in Humans and Animals, Iowa State University Press 2002