Tumors and related lesions of the retinal pigment epithelium (RPE) include congenital hypertrophy of the RPE (CHRPE), hyperplastic RPE lesions associated with familial adenomatous polyposis, congenital simple hamartoma, combined hamartoma, pseudocancerous reactive hyperplasia, benign epithelioma (adenoma), and malignant epithelioma (adenocarcinoma). CHRPE is further divided into solitary and multifocal variants, the latter also known as congenital grouped pigmentation or “bear tracks” (1).

Solitary CHRPE is a well-known fundus condition that has been the subject of considerable attention in the ophthalmic literature (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Although it is believed to be congenital, the median age at diagnosis is 45 years (2). This late diagnosis may be because the condition is generally asymptomatic and located in midperipheral or peripheral fundus and may remain undetected on routine fundus examination. It is usually a solitary lesion that, unlike choroidal nevus and melanoma, has no recognized predilection for race.

The term CHRPE has also been applied to a somewhat different multifocal fundus condition that has a high association with familial adenomatous polyposis (FAP) and bowel cancer (1,21), a subject to be discussed later. That choice of terminology is unfortunate because the typical solitary CHRPE apparently is not associated with an increased incidence of FAP or gastrointestinal malignancy (8).

A review of 330 cases of solitary CHRPE provided additional information regarding this condition (2). It appears clinically as a well-demarcated flat to minimally elevated fundus plaque that can range from a black homogeneous lesion to a completely depigmented lesion (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). As mentioned earlier, most are located in the midperipheral or peripheral fundus. Only 2% are found in the macular or peripapillary region. The lesion is predominately pigmented in 88% and nonpigmented in 12% of cases. The median largest basal diameter is 4.5 mm. Well-defined depigmented foci, called lacunae, are present in 43% of the pigmented CHRPE. Most solitary CHRPE lesions have a typical depigmented ring or “halo” around the margin. The lacunae show enlargement in 32% of cases after a mean follow-up of 5 years (2). The majority of solitary CHRPE show slightly increased diameter, as observed in 74% to 83% of cases followed >5 years in two reported series (2,6).

Concerning differential diagnosis, the large lesions, particularly those in the peripheral fundus, can appear similar to choroidal melanoma. The peripheral lesions generally give the false impression ophthalmoscopically that they are quite elevated. In a series of 330 cases, the referral diagnosis was choroidal nevus in 26%, choroidal melanoma in 15%, and nonspecified fundus lesions in 48%. The correct diagnosis of CHRPE was submitted in only 9% of cases. The clinical features described here are different from those of nevus or melanoma, and the diagnosis readily can be made by the experienced observer.

Recent reports have provided further information about the potential of solitary CHRPE to spawn a nodular growth pattern (9). In perhaps 2% of cases, such a nodular growth develops in the area of CHRPE (2). The growth the nodular growth gradually acquires a retinal feeding artery and draining vein and produces yellow intraretinal exudation and exudative retinal detachment (10). This pattern is identical to the adenoma of the RPE to be described subsequently. In one case that was managed by eye wall resection, the growing amelanotic nodular lesion arising from solitary CHRPE proved to be a low-grade malignant epithelioma (adenocarcinoma) of the RPE (10). A similar case was subsequently reported (15). The subject is discussed later under the section on epitheliomas of the RPE.

Fluorescein angiography and indocyanine green angiography generally show blockage of fluorescence throughout most of the sequence. Characteristically, there is persistent hypofluorescence of the pigmented areas and transmission of choroidal fluorescence through the depigmented areas throughout the angiography sequence (1,2,4). Ultrasonography is nondiagnostic, but in many cases, it shows the lesion to be about 0.5 to 1 mm thick. Visual field results range from a mild relative scotoma to an absolute field defect, usually depending on the size of the lesion. Optical coherence tomography shows overlying retinal thinning, loss of photoreceptors, and moderate relative shadowing of the underlying choroid, but the findings are nondiagnostic (19). The lesion cannot generally be detected with CT or MRI.

Histopathologically, the RPE cells in CHRPE are taller and more densely packed with spherical melanosomes as compared to the normal RPE, which has smaller, more elliptically shaped melanosomes. There appears to be a combination of cellular hyperplasia and hypertrophy. There is overlying atrophy of the photoreceptors (5).

The management of solitary CHRPE is simple periodic observation. If a small nodular growth should evolve, it can often be observed for a period of time because progression is very slow and does not usually affect the patient’s vision. If such a nodule produces exudation or subretinal fluid, laser photocoagulation or cryotherapy can be considered to stop the progression of the leakage. If such a growth should produce surface wrinkling retinopathy in the macular region, vitrectomy and membrane peeling should be considered. The prognosis for CHRPE is generally excellent.

Solitary CHRPE can show considerable variation in color, size, and shape.

In some instances, solitary congenital hypertrophy of the retinal pigment epithelium seems to lose its pigmented appearance and appear predominantly amelanotic. This may correspond with coalescence of the depigmented lacunae. Examples are shown.

Lloyd WC III, Eagle RC, Shields JA, et al. Congenital hypertrophy of the retinal pigment epithelium: electron microscopic and morphometric observations. Ophthalmology 1990;97:1052-1060.

With optical coherence tomography, congenital hypertrophy of the retinal pigment epithelium typically shows retinal thinning and loss of photoreceptors in the overlying sensory retina. The more pigmented lesions tend to block light, and the less pigmented lesions tend to transmit light. Correlations are shown.

Shields CL, Materin MA, Walker C, et al. Photoreceptor loss overlying congenital hypertrophy of the retinal pigment epithelium by optical coherence. Ophthalmology 2006;113:661-665.

The multifocal variant of CHRPE is also known as congenital grouped pigmentation of the retina or “bear tracks” (1, 2, 3, 4, 5, 6, 7, 8, 9). It is generally a nonhereditary, sporadic condition, but it has been observed in a mother and daughter (7). There are usually no related ocular abnormalities, but it has been observed in the opposite eye of a patient with persistent hyperplastic primary vitreous (8), retinoblastoma (4), neurofibromatosis (1), and Coats disease (3). These findings are possibly coincidental.

Multifocal CHRPE is characterized by several groups of well-delineated, flat, slate-gray lesions that usually assume a sector distribution in the fundus. Each group consists of from 3 to 30 individual pigmented lesions that vary from 0.1 to 3 mm in diameter, with the larger lesions located more peripherally. Each individual lesion is similar to unifocal congenital hypertrophy of the RPE, but is usually smaller than the unifocal type and does not show the lacunae or haloes of depigmentation. The lesions are sometimes clinically nonpigmented, in which case they have been called “polar bear tracks” (9). These typical clinical features should serve to differentiate this condition from the numerous other conditions that can be associated with multiple pigmented lesions in the fundus. Retinal electrophysiologic studies are normal in multifocal CHRPE (6). The lesions tend to remain stable.

As mentioned earlier, a close relationship has recently been recognized between multiple small pigmented fundus lesions and familial adenomatous polyposis and Gardner syndrome, conditions associated with familial colonic cancer. The fundus lesions have been called CHRPE, but they are actually different from multifocal CHRPE in that they are bilateral, have a more haphazard distribution, and often have more irregular or jagged borders. There appears to be no association with the typical forms of CHRPE described here and these cancer syndromes (5). This subject is discussed further in the next section.

The histopathology of multifocal CHRPE is very similar to that of solitary CHRPE (3,4). However, light and electron microscopy have suggested that the pigment granules retain their normal ellipsoid configuration, and hypertrophy and hyperplasia were not significant features (3,4).

Multifocal CHRPE requires no treatment and can be observed as part of routine ocular examination. The prognosis is excellent.

Multifocal congenital hypertrophy of the retinal pigment epithelium is also known as congenital grouped pigmentation of the retina or “bear tracks.” Other than being multifocal, it is similar clinically and histopathologically to solitary CHRPE. Like the solitary form, it can be deeply pigmented or nonpigmented, but the depigmented variant is less common. It often assumes a sector distribution, with the small lesions located closer to the optic disc and large lesions toward the peripheral fundus.

Regillo CD, Eagle RC Jr, Shields JA, et al. Histopathologic findings in congenital grouped pigmentation of the retina. Ophthalmology 1993:100:400-405.

This condition has a strong association with familial adenomatous polyposis, an autosomal dominant condition in which almost 100% of patients develop colon cancer (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). It is unfortunate that the term CHRPE was used to describe this fundus condition by those who first made this association (3), because neither solitary nor multifocal CHRPE is associated with an increased incidence of colon cancer (4). To minimize confusion, we choose to call this condition “retinal pigment epithelial hamartomas associated with familial adenomatous polyposis” (RPEH-FAP). About 70% of patients with FAP have these characteristic fundus lesions, which represent the hallmark of a life-threatening familial cancer (14,17,18).

Many ophthalmologists have used the term Gardner syndrome to describe the association of these fundus lesions with bowel cancer. However, Gardner syndrome is defined as FAP plus extracolonic manifestations, including osteomas, desmoid tumors, cutaneous cysts, and several other tumors. Hence, all patients with Gardner syndrome have FAP, but patients with FAP do not necessarily have Gardner syndrome. There is also a close relationship between RPEH-FAP and central nervous system gliomas (Turcot syndrome) (6,16).

RPEH-FAP has characteristic ophthalmoscopic features. Unlike solitary CHRPE, the lesions are multiple and bilateral and their margins are often less well defined. Unlike multifocal CHRPE, they are randomly dispersed and do not have a sector distribution, and they have irregular depigmented margins, sometime forming a fish-tail or comma configuration (4,13). Some have proposed that the presence of three or more such lesions is diagnostic of FAP (18), but some patients have many more, even hundreds of lesions bilaterally.

Histopathologically, RPEH-FAP has been identified to have one of three basic configurations: a monolayer of hypertrophic cells, a mound of RPE cells interposed between the RPE basement membrane of the inner collagenous layer of Bruch’s membrane, or a multilayered mound of hyperplastic cells (8). It is believed to indicate a generalized defect in melanogenesis. The gene for FAP has been identified on the long arm of chromosome 5 (5q21) (18).

The management of RPEH-FAP is periodic observation only. However, the almost universal development of colon cancer in affected patients warrants close scrutiny for and early management of that malignancy. Affected patients, particularly those with a family history of colon cancer, should have periodic colonoscopy and removal of suspicious polyps.

Multifocal lesions of hypertrophy and hyperplasia of the RPE are known to be a hallmark of patients with familial adenomatous polyposis (FAP) and Gardner syndrome, familial conditions that predispose the patient to colorectal cancer. Gardner syndrome consists of FAP with extracolonic manifestations, like desmoid tumors, osteomas, and other benign tumors. Examples of RPEH-FAP are shown.

1. Romania A, Zakov N, McGannon E, et al. Congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis. Ophthalmology 1989;96:879-884.

2. Whitson WE, Orcutt JC, Walkinshaw MD. Orbital osteoma in Gardner’s syndrome. Am J Ophthalmol 1986; 101;236-241.

The RPE has a marked propensity to undergo reactive hyperplasia as a result of ocular insults such as inflammation or trauma. In most instances, RPE hyperplasia is small and typical and does not pose a diagnostic problem. On occasion, such RPE proliferation can simulate a pigmented neoplasm such as choroidal or ciliary body melanoma or true neoplasms of the RPE (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13).

Pseudoneoplastic reactive hyperplasia of the RPE can assume a number of clinical appearances. It can appear as a diffuse or sessile lesion or as a nodular mass. Its dark black color and associated signs of prior inflammation or trauma can help to differentiate the lesion from choroidal melanoma. Secondary retinal detachment is uncommon. Even though this lesion is relatively stable, a few cases have been observed in which small focal areas of RPE hyperplasia have shown evolution into a nodular tumor that transgresses the retina into the vitreous cavity (12). In rare instances, presumed reactive hyperplasia of the RPE can even extend extrasclerally (13).