—  SPECIALTY CONFERENCE  —

Ophthalmic Pathology

Case 2 - Uveal Melanoma

J. Douglas Cameron
Armed Forces Institute of Pathology
Washington, DC





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Clinical History
78 year-old woman presenting with vitreous hemorrhage of the right eye. Subretinal hemorrhage was identified and thought to be due to subretinal neovascularization of age- related macular degeneration associated with a dense subretinal scar. The lesion increased in size. Ultrasound was not diagnostic, however, because of the risk of intraocular tumor the globe was enucleated.

Pertinent Laboratory Data:

Best corrected vision of the right eye was hand motions. The intraocular pressure was 21 mm Hg. Age-related macular degeneration was present in the left eye that had reduced her best corrected vision to 20/60.

Case 2 - Figure 1
Striking spindle cell proliferation.
Case 2 - Figure 2
Undulating growth of neoplastic cells, most of which have a spindle cell morphology.
Case 2 - Figure 3
High-power view of prior illustrations showing focal vague tendency to form whorls.

Case 2 - Figure 4
Uveal melanoma with typical overlying retinal detachment
Case 2 - Figure 5
Densely cellular aggregates of spindle cells separated by a looser myxoid component.
Case 2 - Figure 6
Whole-mount preparation of globe with uveal melanoma

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Most choroidal melanocytic nevi are located in the posterior half of the eye. This lesion is identified by ophthalmoscopy as a hyperpigmented, round to oval region of the posterior uvea that does not distort the contour of the overlying retina. Generally the lesions range in size between 1.5 and 5.0 mm in diameter although smaller and much larger nevi can occasionally be present. Benign nevi are generally less than 2.0 mm in thickness. Choroidal nevi are found in 5-30% of the normal population and may rarely be multiple unilateral or bilateral. The lesions are composed of benign appearing nevus cells that occasionally distort the choriocapillaris and can cause minimal degenerative changes of the retinal pigment epithelium (drusen), but do not extend through Bruch's membrane into the subretinal space as is the case with malignant lesions. The nevus cells may be plump polyhedral cells that are maximally pigmented, spindle- shaped with variable amounts of pigment, or balloon cells with foamy cytoplasm. Mitotic figures are absent. Transformation to melanoma of the uveal tract is possible but the conversion rate has been calculated to be in the range of 1 case of melanoma in 8850 cases of choroidal nevus. Many, if not most, cases of uveal melanoma are thought to arise de novo.

Differential Diagnoses:
Nevus versus melanoma

Final Diagnosis:
Uveal Melanoma


Case Discussion:
The uvea is the vascular coat of the eye which normally contains dendritic melanocytes to absorb stray light and assist retinal function. This layer is between the retina and sclera and extends from t he papillary margin to the border of the optic disc. The uveal tract is divided into distinct regions: iris, ciliary body and choroid. Melanocytic tumors may arise in any portion of the uveal tract. Some of these tumors are easy to detect clinically, such as those of the iris. However, some regions of the uveal tract, such as the ciliary body, are difficult to examine clinically making diagnosis difficult and often delayed.

The benign variant is a melanocytic nevus composed of abnormal melanocytes that are generally maximally pigmented. An iris ephelis (freckle) is an accumulation of normal-appearing melanocytes on the surface of the iris and there is no malignant potential. Iris ephelae are found in 60% of the population with the highest prevalence in white persons. The iris nevus, in contrast, is located in the substance of the iris stroma and may distort the surrounding architecture of the iris, e.g. pupil margin irregularity. Iris nevi are found in 5% of the population and although the lesions are congenital there is a tendency to become more pigmented at the time of puberty an appear acquired. Most are located in the inferior regions of the iris. Lisch nodules of neurofibromatosis type I are localized melanocytic nevi. There is a small risk of malignant transformation to iris melanoma. The most reliable sign of malignant transformation is documented growth. The growth rate is generally very slow; years to decades. Distortion of the pupil contour, extension into the anterior chamber angle and even the presence of pigmented adjacent episcleral tissue are not reliable signs of a malignant lesion.

Most choroidal melanocytic nevi are located in the posterior half of the eye. This lesion is identified by ophthalmoscopy as a hyperpigmented, round to oval region of the posterior uvea that does not distort the contour of the overlying retina. Generally the lesions range in size between 1.5 and 5.0 mm in diameter although smaller and much larger nevi can occasionally be present. Benign nevi are generally less than 2.0 mm in thickness. Choroidal nevi are found in 5-30% of the normal population and may rarely be multiple unilateral or bilateral. The lesions are composed of benign appearing nevus cells that occasionally distort the choriocapillaris and can cause minimal degenerative changes of the retinal pigment epithelium (drusen), but do not extend through Bruch's membrane into the subretinal space as is the case with malignant lesions. The nevus cells may be plump polyhedral cells that are maximally pigmented, spindle-shaped with variable amounts of pigment, or balloon cells with foamy cytoplasm. Mitotic figures are absent. Transformation to melanoma of the uveal tract is possible but the conversion rate has been calculated to be in the range of 1 case of melanoma in 8850 cases of choroidal nevus. Many, if not most, cases of uveal melanoma are thought to arise de novo.

Uveal melanoma is uncontrolled growth of uveal dendritic melanocytes with the capacity for wide-spread fatal metastasis. These tumors do not arise from the retinal pigmented epithelium (the pigmented cells of the retina derived directly from neuroectoderm that biochemically support the retina). Uveal melanoma is the most common malignant intraocular tumor of adults, but is in fact extremely rare occurring in 4.3 to 10.9 cases per million population. White races are at greater risk than pigmented races. All ages and both sexes are at risk with a definite predilection for older ages and a slight predilection for males. The incidence at the age of diagnosis rises steadily to age 70 years and then plateaus or slightly diminishes after that time. There has been no increase in the overall incidence of uveal melanoma over the past 50 years as has been experienced with cutaneous melanoma. Exposure to ultraviolet light appears to play no role in the generation of uveal melanoma.

Melanoma of the eye presents in most cases as a dome-shaped elevation of the uveal tract. Both amelanotic and hyperpigmented lesions are encountered. Early lesions have similar features to a long list of space-occupying entities of the uveal tract, however, the diagnostic accuracy of a clinical diagnosis of uveal melanoma by clinical criteria alone is over 99%. Melanoma of the uveal tract, in contrast with cutaneous melanoma, tends to thicken toward the center of the eye before of extending horizontally through the adjacent choroid. Eventually melanoma cells will extend through Bruch's membrane into the subretinal space causing the retina to detach. Up to the point of retinal detachment most persons with uveal melanoma are asymptomatic. Visual symptoms occur with distortion, detachment or invasion of the retina. Generally uveal melanoma, unless necrotic, causes no ocular pain.

Conclusion(s):
The uvea is the vascular coat of the eye which normally contains dendritic melanocytes to absorb stray light and assist retinal function. This layer is between the retina and sclera and extends from t he papillary margin to the border of the optic disc. The uveal tract is divided into distinct regions: iris, ciliary body and choroid. Melanocytic tumors may arise in any portion of the uveal tract. Some of these tumors are easy to detect clinically, such as those of the iris. However, some regions of the uveal tract, such as the ciliary body, are difficult to examine clinically making diagnosis difficult and often delayed.

References:
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  4. McLean IW, Zimmerman LE, Evans RM. Reappraisal of Callender's spindle a type of malignant melanoma of choroid and ciliary body. Am J Ophthalmol. 1978;86(4):557-564.

  5. McLean IW, Foster WD, Zimmerman LE, Gamel JW. Modifications of Callender's classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol. 1983;96(4):502-509.

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  7. McLean IW, Saraiva VS, Burnier MN, Jr. Pathological and prognostic features of uveal melanomas. Can J Ophthalmol. 2004;39(4):343-350.

  8. McLean MJ, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol. 1977;95(1):48-58.

  9. Whelchel JC, Farah SE, McLean IW, Burnier MN. Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci. 1993;34(8):2603-2606.

  10. Zimmerman LE, McLean IW. Metastatic disease from untreated uveal melanomas. Am J Ophthalmol. 1979;88:524-534.

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