Tumors of the Retinal Pigment Epithelium
JERRY A. SHIELDS, MD and CAROL L. SHIELDS, MD

The retinal pigment epithelium (RPE) often undergoes reactive hyperplasia secondary to trauma, inflammation, and other ocular insults. Although less common, it can spawn a variety of tumors and related lesions.^1,2 The main tumors include congenital hypertrophy of the RPE, congenital simple hamartoma, combined hamartoma, adenoma, and adenocarcinoma.

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a common fundus condition that is usually detected as an incidental finding. It can be solitary or multifocal, the latter is congenital grouped pigmentation or "bear tracks." Since the multifocal variant is not important in the differential diagnosis of fundus tumors, it is not discussed further in this chapter.

	Figure 1. Congenital hypertrophy of the RPE with halo superiorly and central depigmented lacuna.

Clinical Features

Solitary CHRPE is characteristically a unilateral, deeply pigmented, flat lesion with a sharply demarcated margin.^1-3 It ranges from 1­6 mm in diameter and is often uniformly black. It may have a well-delineated marginal halo and depigmented lacunae within the lesion (Figure 1). Con-genital hypertrophy of the RPE is usually stationary, but it may occasionally increase in diameter or spawn an elevated nodule that may represent adenoma or adenocarcinoma.^4,5

Diagnostic Approaches

The appearance of CHRPE should enable the clinician to make the diagnosis and differentiate it from choroidal melanoma.^1-3 In addition, fluorescein angiography reveals hypofluorescence throughout all phases of the angiogram except for the haloes and lacunae, which show only transmission hypofluorescence.

Pathology

Histopathologically, CHRPE consists of a focal area in which the RPE cells are taller and more densely packed with melanosomes that obscure their nuclei.^1,2 The individual melanosomes are larger and spherical as compared to those of the normal RPE, which are smaller and more elliptical. The depigmented lacunae correspond to areas where the melanosomes are sparser.

Management

Treatment is not indicated for solitary CHRPE. It is usually asymptomatic and should be observed periodically as part of a routine ocular examination. Even CHRPE that spawn slow-growing nodular elevations can usually be followed for a period of time.

CONGENITAL SIMPLE HAMARTOMA OF THE RPE

Congenital simple hamartoma of the RPE (CSHRPE) is an uncommon lesion that has distinctive clinical features.⁶

	Figure 2. Congenital simple hamartoma of RPE in foveal region.

Clinical Features

Congenital simple hamartoma of the RPE appears ophthalmoscopically as a small localized, elevate black lesion that is usually located in the foveal region (Figure 2). It is usually <1 mm in diameter. Unlike CHRPE, it is distinctly elevated. The lesion generally remains stationary and is not known to grow.

Diagnostic Approaches

With fluorescein angiography, CSHRPE is typically hypofluorescent throughout the angiogram. It is generally too small to be detected with ultrasonography. We have evaluated 1 case with ocular coherence tomography and found the lesion to be highly reflective.

Pathology

The pathology of CSHRPE is not well established. We believe that it is a mass composed of a proliferation of the RPE, with benign cytologic features.

Management

Congenital simple hamartoma of the RPE usually requires no active management. It may induce some visual loss, but the foveal location limits the use of laser photocoagulation or other methods.

COMBINED HAMARTOMA OF THE RPE AND SENSORY RETINA

Combined hamartoma of the RPE and sensory retina is a well-known fundus lesion that is difficult to categorize.^1,2,7 Although it is considered by some to represent a hamartoma, the pathogenesis is not clearly established and a somewhat similar lesion can result from intraocular inflammation or trauma, and can be seen in patients with type 2 neurofibromatosis. The fact that many cases are diagnosed in young children and infants lends support to the hypothesis that the lesion is congenital.

	Figure 3. Juxtapapillary combined hamartoma of the retina and RPE.

Clinical Features

The clinical appearance of a combined hamartoma varies according to whether the lesion is in a juxtapapillary or a peripheral location.^1,2,7 The juxtapapillary lesion characteristically appears as a solitary mass adjacent to or overlying portion of the optic disc, with variable amounts of pigmentation, vascularity, and gray-white tissue (Figure 3). The retinal vessels within and overlying the lesion are often stretched or tortuous and are obscured by white fibroglial tissue at the level of the vitreoretinal interface. This surface glial tissue tends to gradually contract, leading to further tortuosity of the blood vessels and retinal striae, which may distort the fovea and cause visual loss. Vitreoretinal traction can lead to accumulation of subfoveal exudation, secondary retinoschisis, and retinal hole.

The peripheral combined hamartoma, which can be located in any portion of the fundus, appears as an elevated gray ridge concentric to the ora serrata. It characteristically produces dragging of the large retinal vessels toward the lesion. However, peripheral to the lesion the major retinal vessels appear straight and stretched. The 2 most important lesions to differentiate from the combined hamartoma are the choroidal nevus and choroidal melanoma.^1,2

Diagnostic Approaches

The diagnosis of combined hamartoma is usually made on the basis of ophthalmoscopic findings, and except for fluorescein angiography, ancillary studies are not particularly useful.^1,2,7 During the arterial phase, there is relative hypofluorescence of the lesion. By the early venous phase, fine blood vessels may be recognized within the lesion.

Pathology

Histopathologically, combined hamartoma consists of thickening of the sensory retina and optic nerve from replacement of these tissues by glial cells, vascular tissue, and sheets of pigment epithelial cells. The contraction of the fibroglial tissue accounts for the apparent preretinal membrane and tortuosity of retinal vessels seen clinically.

Management

There are no established guidelines for management of combined hamartoma. In those cases that produce visual loss because of retinal traction in the fovea, vitrectomy and membrane peeling have been used in hopes of stabilizing or improving the visual acuity.

ADENOMA AND ADENOCARCINOMA

As mentioned earlier, the RPE has a marked tendency to undergo reactive hyperplasia, but little tendency toward true neoplasia. However, it can occasionally spawn either benign adenomas or malignant adenocarcinomas.^1,2,8 Since both have similar clinical behavior with local growth and no tendency to metastasize, they will be considered together in this discussion.

	Figure 4. Peripheral adenoma of the RPE.
	Figure 5. Peripheral adenoma of the RPE with large dilated feeder vessels.
	Figure 6. Juxtapapillary adenoma of the RPE. The diagnosis was confirmed histopathologically after the eye was removed postmortem.

Clinical Features

Adenoma of the RPE appears as an oval shaped abruptly elevated, usually pigmented mass (Figure 4). Unlike choroidal melanoma, it has no flat nevus at its base, but rather arises abruptly from the adjacent normal RPE. The affected eye often has vitreous cells due to inflammation. It is often uncertain whether the inflammation induces the development of the tumor or whether the tumor induced the inflammation. As it enlarges, adenoma of the RPE can assume a retinal blood supply with large, dilated tortuous feeding, as well as draining blood vessels similar to those seen with the retinal capillary hemangioma (Figure 5). Intraretinal and subretinal exudation are commonly found adjacent to the tumor. These features differentiate adenoma of the RPE from choroidal melanoma. The tumor is usually situated in the peripheral retina, but can occur adjacent to the optic disc (Figure 6).

Diagnostic Approaches

Fluorescein angiography of an adenoma of the RPE can vary from case to case. Some show relative hypofluorescence and mild late staining. The tumor does not show the double circulation that characterizes many choroidal melanomas. A scan ultrasonography generally shows moderately high internal reflectivity and a B-scan demonstrates an irregular contour with acoustic solidity. In cases where the diagnostic is uncertain, a transocular fine needle biopsy can assist in the diagnosis.

Pathology

Histopathologically, adenoma of the RPE usually shows cords of proliferating RPE cells, separated by fibrous stroma. Bleached preparations demonstrate the tumor cells to be large and polyhedral with eccentric round to oval nuclei and abundant granular cytoplasm. Adenocarcinoma of the RPE exhibits similar patterns, but more pleomorphic cells characterize it.

Management

Small suspected adenoma of the RPE can usually be safely observed and treatment withheld until growth is documented. Irradiation can be attempted, but the results have not been clearly established. A progressive lesion may sometimes require enucleation.

CONCLUSIONS

Tumors and related lesions that arise from the pigment epithelium include solitary CHRPE, reactive hyperplasia, combined hamartoma, adenoma, and adenocarcinomas. Most of these lesions are generally benign in their clinical behavior, but some can show slow growth and ocular complications. They must be differentiated from choroidal melanoma and other pigmented fundus lesions.

REFERENCES

1. Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia, PA: WB Saunders; 1992:437-460.

2. Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In Shields JA, Shields CL, eds. Atlas of Intraocular Tumors. Philadelphia, PA: Lippincott, Williams and Wilkins; 1999:287-307.

3. Shields CL, Mashayekhi A, Ho T, Cater J, Shields JA. Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features and frequency of enlargement in 330 patients. Ophthalmology. In press.

4. Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital hypertrophy of the retinal pigment epithelium. Arch Ophthalmol. 2000;118:637-641.

5. Shields JA, Shields CL, Eagle RC Jr, Singh AD. Adenocarcinoma arising from congenital hypertrophy of the retinal pigment epithelium. Arch Ophthalmol . 2001;119:597-602.

6. Shields CL, Shields JA, Marr BP, Sperber DE, Gass JM. Congenital simple hamartoma of the retinal pigment epithelium. A study of five cases. Ophthalmology. 2003;110:1005-1011.

7. Schachat AP, Shields JA, Fine SL, et al. Combined hamartoma of the retina and retinal pigment epithelium. Ophthalmology. 1984;91:1609-1615.

8. Shields JA, Shields CL, Gunduz K, Eagle RC Jr. Neoplasms of the retinal pigment epithelium. The 1998 Albert Ruedemann Sr. Memorial Lecture. Part 2. Arch Ophthalmol.1999;117:601-608.

From the Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA. None of the authors has any financial interest in the information contained in this article.