Chapter 151 – Uveal Nevus
JAMES J. AUGSBURGER
J. WILLIAM HARBOUR
JOHN R. GONDER
• Primary benign acquired melanocytic tumor of uvea.
• Brown or fleshy iris mass usually 3?mm or less in diameter and 0.5?mm or less in thickness.
• Gray to brown (melanotic) or tan (amelanotic) choroidal mass usually 5?mm or less in diameter and 1?mm or less in thickness.
• Anterior uveal nevi: ectropion iridis and pupillary peaking.
• Posterior uveal nevi: drusen and retinal pigment epithelial alterations on surface of choroidal tumor; occasional shallow nonrhegmatogenous retinal detachment that overlies and surrounds choroidal tumor.
The uveal nevus is a benign tumor that arises from melanocytic cells derived from the neural crest. Uveal nevi occur most commonly in the choroid, but similar lesions also occur in the iris, ciliary body, and optic disc.
EPIDEMIOLOGY AND PATHOGENESIS
The uveal nevus is unquestionably the most common primary intraocular tumor. In Caucasians, it has been estimated that approximately 20% of persons older than 50 years have at least one choroidal nevus. If small melanocytic iris lesions are counted as nevi, 30–50% of eyes have at least one uveal nevus. Most uveal nevi are likely to be congenital in nature, but they usually do not become pigmented and detectable clinically until after childhood. The frequency of clinically evident uveal nevi increases with advancing age. Uveal nevi are much more common in persons of lightly pigmented races. They appear to be equally common in men and women.
Uveal nevi are commonly regarded as precursor lesions to uveal malignant melanoma. Although some uveal nevi unquestionably undergo malignant change, comparative age-specific prevalence estimates for uveal nevi and uveal melanomas suggest that only about 1 in 4000–5000 uveal nevi actually does so.
Most uveal nevi are asymptomatic. Macular choroidal nevi, however, can cause visual loss in the affected eye.
The typical iris nevus appears as a localized melanotic stromal lesion of the iris ( Fig. 151-1 ). It can involve any portion of the iris from the pupillary margin to the iris root. The typical iris nevus is 3?mm or less in diameter and 0.5?mm or less in thickness;
Figure 151-1 Typical iris nevus. Thin, dark brown iris lesion does not cause pupillary irregularity.
Figure 151-2 Typical choroidal nevus. Thin gray-brown choroidal lesion has a few small drusen on its surface.
however, larger iris nevi are documented from time to time. Iris nevi can cause pupillary peaking, focal ectropion iridis, or both, but they are rarely associated with abnormal iris vasculature.
The typical choroidal nevus appears as a small gray to brown choroidal tumor with a bland surface appearance ( Fig. 151-2 ). Many choroidal nevi exhibit characteristic surface alterations such as drusen and retinal pigment epithelial pigment clumping ( Fig. 151-3 ). Most choroidal nevi are 5?mm or less in basal diameter and 1?mm or less in thickness, but occasional lesions of this type attain a basal diameter of 10?mm or more, a thickness of 3?mm or more, or both. Blurred or distorted vision attributable to a choroidal nevus may be the result of an accumulation of serous subretinal fluid, cystic degeneration of the retina overlying a macular choroidal nevus, or choroidal neovascularization. Occasional choroidal nevi have a halo appearance characterized by a golden orange marginal zone that surrounds the typically gray to brown central zone.
Figure 151-3 Large choroidal nevus. This mildly elevated (thickness 1.5?mm) melanotic choroidal tumor has prominent drusen and retinal pigment epithelial pigment clumps on its surface.
Figure 151-4 Melanocytoma of optic disc.
A special type of uveal nevus is the melanocytoma of the optic disc. This lesion is usually composed entirely of maximally pigmented, polyhedral nevus cells (magnocellular nevus cells). Clinically, the melanocytoma is a brown to black tumor that involves the substance of the optic disc ( Fig. 151-4 ). The surface of the lesion commonly appears striated because of insinuation of the darkly pigmented cells of the tumor between axons in the nerve fiber layer. If the melanocytoma compresses the optic disc, it can produce prominent visual field defects. Lesion enlargement can occur but is usually slow. Magnocellular nevi also occur in the choroid, ciliary body, and iris, but such nevi cannot be differentiated clinically from nevi of other histopathological types.
DIAGNOSIS AND ANCILLARY TESTING
Suspected melanocytic lesions of the iris are usually documented photographically shortly after detection and then monitored for subsequent enlargement or other worrisome changes that might signal malignant behavior. Fluorescein angiography and indocyanine green angiography have little differential diagnostic or prognostic value. Ultrasound biomicroscopy is used to measure the size and extent of an iris tumor.
Suspected melanocytic tumors of the choroid (i.e., nevi versus melanomas) are generally evaluated by ultrasonography and fluorescein angiography. Ultrasonography allows the ophthalmologist to assess the precise thickness of the lesion, identify its reflectivity pattern, and rule out scleral invasion and trans-scleral tumor extension. Fluorescein angiography and indocyanine green angiography assess the presence or absence of prominent blood vessels within the tumor. Most benign choroidal nevi do
Differential Diagnosis of Uveal Nevi
Differential Diagnosis of Iris Nevus
Malignant melanoma of iris
Metastatic carcinoma to iris
Neuroepithelial cyst of iris
Iris nodules of iridocorneal endothelial syndrome
Leiomyoma of iris
DIFFERENTIAL DIAGNOSIS OF CHOROIDAL OR CILIARY BODY NEVUS
Uveal malignant melanoma
Metastatic carcinoma (if lesion is amelanotic or hypomelanotic)
Circumscribed choroidal hemangioma
Choroidal neurilemoma (schwannoma)
Congenital unifocal hypertrophy of retinal pigment epithelium
Reactive hyperplasia of retinal pigment epithelium
Subretinal or suprachoroidal hematoma
not have prominent intralesional blood vessels, but most choroidal melanomas do. Consequently, most choroidal nevi appear totally hypofluorescent throughout the angiogram except at sites of drusen and retinal pigment epithelial depigmentation. With indocyanine green angiography, most choroidal nevi appear totally nonfluorescent throughout the study. The full basal extent of a choroidal nevus is defined better by indocyanine green angiography than by fluorescein angiography. For worrisome lesions, fine-needle aspiration biopsy can be used to determine the pathological nature of the tumor before therapeutic intervention. Melanotic choroidal lesions more than 1.5?mm thick can usually be biopsied successfully using a transvitreal, bent-needle technique.
Most of the important lesions in the differential diagnosis of uveal nevi are listed in Box 151-1 . Uveal melanoma is unquestionably the most important lesion in the differential diagnosis.
Two important systemic disorders are associated with melanocytic choroidal nevi. In some patients who have neurofibromatosis type 1, multiple uveal nevi develop in both eyes. These lesions must be differentiated from the small, tan, melanocytic iris lesions (Lisch nodules) that arise multifocally from the anterior surface of the iris. Lisch nodules appear to be nodular aggregates of dendritic melanocytes and not true nevi. They usually become evident by the age of 10–15 years and are highly characteristic of neurofibromatosis type 1.
In patients who have the syndrome of bilateral diffuse melanocytic proliferation associated with systemic carcinoma, multiple acquired melanocytic uveal nevi frequently arise in both eyes in response to some as yet undetermined substance elaborated by an underlying but often occult systemic cancer.
Baseline Systemic Evaluation
Because uveal nevi are benign lesions, baseline systemic evaluation is generally not recommended in patients who have such lesions. If changes in a presumed uveal nevus prompt its reclassification as a probable malignant melanoma, a baseline systemic evaluation appropriate to a uveal melanoma (see Chapter 147 ) becomes warranted.
Figure 151-5 Histopathology of choroidal nevus. Note the spindle-shaped nuclei, absent and prominent nucleoli, uniformity of tumor cells, and prominent intracytoplasmic melanin that characterize spindle cell choroidal nevus.
The uveal nevus is composed of atypical melanocytic cells that are benign by histopathological criteria ( Fig. 151-5 ). Several different types of uveal nevus cells are known. Spindle nevus cells are fusiform melanocytes that typically have a relatively small nucleus and either no nucleolus or a small nucleolus. Spindle nevus cells usually contain relatively few small, intracytoplasmic melanin granules. Magnocellular nevus cells are plump polyhedral melanocytes that typically contain numerous large, intracytoplasmic melanin granules but have completely benign-appearing nuclei. Epithelioid nevus cells are relatively large, spherical melanocytes that contain a variable amount of intracytoplasmic melanin but do not have the nuclear and nucleolar pleomorphism that characterizes epithelioid melanoma cells. Balloon nevus cells are relatively large, spherical melanocytes characterized by a substantial amount of foamy, vacuolated cytoplasm.
The predominant cell type in most iris nevi is the spindle nevus cell. In contrast, the predominant cell type in most choroidal and ciliary body nevi is the magnocellular nevus cell. Many uveal nevi consist of an admixture of more than one cell type. Balloon nevus cells typically occur in the yellow-orange halo that surrounds some choroidal nevi.
Dendritic melanocytes, which occur in some uveal nevi, in Lisch nodules of neurofibromatosis type 1, and in the iris nodules of the Cogan-Reese syndrome and iridocorneal endothelial syndrome, appear to be normal uveal melanocytes and not nevus cells.
The standard management of patients who have choroidal nevi is photographic documentation of the tumor’s appearance, ultrasonographic documentation of its thickness, and periodic re-evaluation to make sure that it remains dormant ( Box 151-2 ). The recommended frequency of follow-up is largely a function of the level of diagnostic certainty and concern about potential malignancy. For very small nevi that appear nonsuspicious, the ophthalmologist may simply recommend re-evaluation within 1–2 years. For slightly larger nevi, the ophthalmologist may recommend re-evaluation within 6–12 months. If concern exists that the lesion may actually be a small malignant melanoma, the patient may be re-examined within 1–3 months. If re-evaluation over that short interval shows no appreciable change in the lesion, subsequent re-evaluations are usually scheduled at increasingly longer intervals. In general, nevi that are suspicious must be followed relatively closely for at least 3–5 years. If no substantial change occurs in the nevus over that interval, most ophthalmologists recommend future follow-up evaluations at approximately yearly intervals. If the nevus remains stable, periodic follow-up examinations will reassure both the patient and the ophthalmologist about the continued dormancy and benign status of the tumor.
Treatment Options for Uveal Nevi
Observation (unless lesion enlarges abruptly or substantially or otherwise changes and is reclassified as uveal melanoma)
Treatment of subretinal fluid involving macula
• Focal laser therapy to angiographically localized leak sites
• Barrier laser around nevus to wall off subretinal fluid
Biopsy or excision of worrisome lesions
• Fine-needle aspiration biopsy
• Incisional biopsy or excision (iridectomy for iris lesions)
Focal laser therapy can be considered for presumed choroidal nevi that are associated with serous macular retinal detachment and distorted or blurred vision. If the fluid fails to disappear or increases, or the visual acuity in the affected eye deteriorates substantially, focal laser treatment to the angiographic leak sites can be used to stimulate fluid reabsorption. If no focal angiographic leak sites are evident and the lesion does not extend beneath the fovea, laser treatment in the form of a barrier of overlapping or confluent laser burns between the nevus and the fovea sometimes walls off the subretinal fluid from the central macula. Alternatively, if the angiogram reveals a choroidal neovascular membrane that overlies the nevus, focal obliterative laser therapy can be employed to eradicate the vascular network. Although some small choroidal melanomas with associated serous subretinal fluid develop nodular eruption through Bruch’s membrane after focal laser treatment to the retinal pigment epithelial leak sites or to a suspected choroidal neovascular membrane that overlies the lesion, no compelling evidence exists that such laser treatment ever induces malignant change in a benign choroidal nevus.
COURSE AND OUTCOME
Most uveal nevi change very little over the course of several years. At the same time, however, many nevi exhibit slight changes in color and surface features or enlarge slightly over long periods of follow-up. Such minor changes should not be considered indicative of malignancy but rather should be considered manifestations of normal growth and aging. Conversely, some benign-appearing melanocytic uveal tumors that are initially diagnosed as nevi eventually exhibit clinical features suggesting that they are in fact malignant melanomas. In such cases, one can never be certain whether the change in the lesion represents more pronounced enlargement of a benign nevus than usually occurs, malignant transformation of a benign nevus to a malignant melanoma, or activation of a malignant melanoma that had been dormant. Substantial tumor enlargement, especially if it occurs over a relatively short time (e.g., 6 months or less), must be regarded as strong circumstantial evidence of the malignancy of the lesion. Such a change usually prompts the ophthalmologist to reclassify the tumor as a malignant melanoma and recommend intervention accordingly.
Features of a melanocytic choroidal lesion that help assure the ophthalmologist of its benign nature include small size (basal diameter <5?mm, thickness <1?mm), homogeneous gray-brown surface coloration, feathered margins that blend almost imperceptibly into the surrounding normal choroid, drusen and retinal pigment epithelial pigment clumping and migration on the surface of the lesion, absence of prominent clumps of orange lipofuscin pigment on the surface of the lesion, absence of overlying serous subretinal fluid, and clinical dormancy of the lesion over long-term follow-up. As with presumed iris nevi, the greater the number of unfavorable features, the greater the concern that the lesion is in fact a melanoma rather than a benign uveal nevus.
By definition, uveal nevi are benign lesions. Therefore, unless malignant change occurs within such a lesion, the affected
patient’s risk of metastasis and tumor-related death is effectively zero. Because the likelihood of malignant transformation by classic uveal nevi appears to be exceptionally low, obliterative treatment of such lesions to prevent possible future malignant transformation is inappropriate.
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