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Arch Ophthalmol. 2002;120:82-85.

The differential diagnosis of malignant melanoma of the uveal tract continues to challenge clinicians. In recent decades, we have come to expect a 95% or better accuracy in the clinical diagnosis of malignant melanoma, and in some centers such as the Wills Eye Institute, Baltimore, Md,¹ and the Mayo Clinic, Rochester, Minn,² 96.3% and 97.7% accuracies, respectively, have been reported. In 1990, a North American prospective randomized multicenter study group, the Collaborative Ocular Melanoma Study (COMS) Group, reported a 99.5% accuracy in the diagnosis of choroidal melanoma.³ By 1998, the COMS had enrolled more than 2300 eyes into the study, and among the 1532 eyes randomized and enucleated, 1527 were found to have a choroidal melanoma, resulting in a diagnostic accuracy of 99.67%.^4-6 The 5 misdiagnosed cases included 4 adenocarcinomas that metastasized to the choroid and 1 choroidal hemangioma. The low misdiagnosis rate in the COMS is a reflection of the level of expertise of the ophthalmologists participating in this study, but it also results from the study aim, which was to include only patients whose tumors could be adequately visualized and were believed to clearly fit the criteria of malignant choroidal melanoma. The COMS reported 2 additional misdiagnosed cases that underwent enucleation after original treatment with iodine I 125 (¹²⁵I) brachytherapy. Both were melanocytomas discovered in eyes that initially had been randomized to ¹²⁵I brachytherapy for presumed melanoma, and both were later enucleated because of tumor growth.³ Similarly, we report an additional case of a choroidal tumor that received ¹²⁵I brachytherapy as primary treatment of presumed malignant melanoma and that was identified as melanocytoma after histopathologic examination of the enucleated specimen.

Report of a Case
A 60-year-old woman was initially examined at the Mayo Clinic in 1990 and was found to have a pigmented 5 x 4.5-mm choroidal lesion exhibiting lipofuscin and a collar-button configuration. Subretinal fluid associated with the tumor extended into the macula, reducing visual acuity (Figure 1). Results of fluorescein angiography demonstrated patchy hypofluorescence and late tissue staining within the tumor. Results of ultrasonography demonstrated a solid lesion with choroidal excavation and low levels of internal reflectivity (A-scan [Figure 2]). The tumor was 2.9 mm thick. In accordance with the patient's strong preference to have the tumor treated with brachytherapy, she was not enrolled in the COMS, and ¹²⁵I brachytherapy was administered. Three years after brachytherapy, extensive radiation retinopathy was observed. Five years after brachytherapy, in 1996, the eye became blind and painful owing to neovascular glaucoma. The tumor measured 3.2 mm in thickness by ultrasonography. The eye was enucleated.

View larger version (21K): [in this window] [in a new window] Figure 1. Fundus photographs showing tumor with collar-button configuration, lipofuscin, and subretinal fluid.

View larger version (47K): [in this window] [in a new window] Figure 2. Results of ultrasonography demonstrating solid lesion with choroidal excavation (A) and low internal reflectivity on A-scan (B).

On gross pathological examination, findings included a black mushroom-shaped mass immediately temporal to the optic nerve, with a measurement of 7 x 7 x 3 mm (Figure 3). Histologically, it corresponded to a heavily pigmented choroidal tumor that had broken through Bruch's membrane to infiltrate the overlying retina (Figure 4). Bleached sections showed a uniform population of large cells with abundant cytoplasm and small, bland nuclei consistent with the diagnosis of melanocytoma (Figure 5). Occasional inconspicuous nucleoli were present. Necrosis and mitotic figures were not seen. The histocytic marker CD68 did not reveal foamy macrophages. Results of electron microscopy showed type II melanocytoma cells with small melanosomes and premelanosomes measuring less than 1 µm in diameter (Figure 6).

View larger version (29K): [in this window] [in a new window] Figure 3. Gross specimen showing the collar-button configuration of heavily pigmented tumor that had broken through Bruch's membrane.

View larger version (108K): [in this window] [in a new window] Figure 4. Medium-power photomicrograph demonstrating the collar-button configuration of the tumor, resulting from the invasion through Bruch's membrane into the retina. Retinal detachment, cystic degeneration, and exudates are observed (hematoxylin-eosin, original magnification x100).

View larger version (69K): [in this window] [in a new window] Figure 5. Bleached sections showing neoplastic cells with small, bland-appearing nuclei and abundant cytoplasm. Necrosis, mitosis, and nucleoli are absent (hematoxylin-eosin, original magnification x200).

View larger version (73K): [in this window] [in a new window] Figure 6. Results of electron microscopy showing type II melanocytoma cells with small melanosomes of less than 1 µm in diameter (lead citrate, original magnification x26 000).

Comment
Melanocytomas of the eye may occur in any location within the uveal tract, but most commonly they arise from pigmented cells that are incorporated within the optic disc.⁷ Melanocytomas of the optic nerve head are generally heavily pigmented and frequently have a feathered black edge that extends into the adjacent retina.⁸ In this typical location, the clinical diagnosis of melanocytoma is usually not a problem. However, the diagnosis of this tumor elsewhere in the uveal tract may prove to be more of a challenge. In the ciliary body or iris, melanocytomas tend to be heavily pigmented, and the correct diagnosis is suspected on the basis of this clinical feature. However, melanocytomas involving the choroid are unusual.⁹ Choroidal melanocytomas have been reported as part of paraneoplastic syndromes (super nevus syndrome or bilateral diffuse uveal melanocytic proliferation syndrome^10-12), and in those cases, they tend to be very dark, multiple, and bilateral, and the correct diagnosis may be suspected clinically.

Several clinical features in our case, eg, the color, the presence of lipofuscin and subretinal fluid, and the collar-button configuration, suggested the clinical diagnosis of choroidal melanoma. In fact, the presence of a collar-button configuration is unusual in any tumor other than malignant melanoma, and its presence alone strongly suggests that diagnosis. However, this finding is not pathognomonic of melanoma; it has been reported in association with melanocytoma¹³ as well as a tumor of the retinal pigment epithelium.¹⁴ Tumor growth in this case also supported the diagnosis of malignant melanoma, as melanocytomas often remain clinically stable except when m occurring with the super nevus syndrome.^{10, 12, 15}

In our case, results of fluorescein angiography and ultrasonography also supported the diagnosis of melanoma. The fluorescein study showed patchy hyperfluorescence and late tissue staining of the tumor. A typical melanocytoma would be expected to obscure background fluorescein significantly, but this was not observed in our case. The ultrasonographic features in our case included a relatively low level ofinternal reflectivity with acoustic hollowing and choroidal excavation, findings characteristic of a melanoma rather than a melanocytoma, which has been observed to have high levels of internal reflectivity.¹⁶

The classic histological appearance of a melanocytoma, such as that seen in our case, is a heavily pigmented neoplasm with abundant cytoplasmic pigment that obscures the nuclear features. Bleached sections disclose large, uniform cells with a distinct cytoplasmic membrane, abundant cytoplasm, and a rounded, small, bland-appearing nucleus that may or may not contain an inconspicuous nucleolus.⁷ The difficulties in differentiating the histological features of benign and malignant pigmented lesions have long been recognized and have been the subject of individual publications.^17-18

Is there an indication to perform a fine-needle aspiration (FNA) biopsy in this case? Fine-needle aspiration biopsy is generally reserved for cases with atypical clinical features, and since this case presented with clinical characteristics typical of melanoma, FNA biopsy was not considered. Even if an FNA biopsy had been performed, we have no guarantee that a conclusive diagnosis could be achieved because of the difficulties in obtaining diagnostic material that properly samples the tumor and because of difficulties interpreting the cells. Shetlar and colleagues¹⁹ reported a case of choroidal neoplasm diagnosed by means of FNA biopsy. In that case, a diagnosis of melanoma was rendered, but at enucleation the tumor proved to be a composite tumor consisting of 2 different cell populations. Melanocytoma occupied one side of the tumor, and malignant melanoma occupied the other.

Melanocytomas are generally easily recognized by ophthalmic pathologists familiar with this entity. Irradiation may alter the histological features of an intraocular tumor, confounding interpretation of the cell type. In case of extensive tumor necrosis, one may not be able to recognize tumor type with certainty. Radiation therapy may produce, in addition to tumor necrosis, a macrophage response with numerous pigment-laden histiocytes. The interpretation of such cells may prove to be a challenge to the pathologist during light microscopy. However, histiocytic markers, eg, CD68, are helpful in this differential diagnosis. Foamy macrophages were not seen in our case, and histological examination of the tumor showed little evidence of necrosis 5 years after brachytherapy. Ultrastructural studies may help support the diagnosis of melanocytoma and differentiate between 2 types of melanocytoma cells. The type II melanocytoma cells containing small melanosomes were seen in our case (Figure 6). These cells are considered more metabolically active than type I cells.²⁰

In conclusion, this case illustrates the difficulty in differentiating a choroidal melanocytoma from a choroidal melanoma on the basis of clinical features alone. It remains uncertain whether the histological features in this case accurately portrayed the tumor characteristics that existed before radiation; however, the absence of necrosis and fibrosis support our impression that this neoplasm was always a melanocytoma that mimicked a malignant melanoma.

AUTHOR INFORMATION
This study was supported in part by a grant from Research to Prevent Blindness, Inc, New York, NY, and in part by the Mayo Foundation, Rochester, Minn.

We thank Bonnie Ronken for secretarial support and Cheryl Hann, MS, for support with the electron microscopy studies.

Dennis M. Robertson, MD; R. Jean Campbell, MD; Diva R. Salomão, MD
Rochester, Minn

Corresponding author and reprints: Dennis M. Robertson, MD, Department of Ophthalmology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: robertson.dennis{at}mayo.edu)

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