The terms “hamartoma,” “choristoma,” “phacoma (mother spot),” and “nevus” are used to describe benign developmental tumors or placoid lesions. Stedman’s Medical Dictionary defines a hamartoma as: “a focal malformation that resembles a neoplasm grossly and even microscopically, but results from faulty development in an organ; it is composed of an abnormal mixture of tissue elements, or an abnormal proportion of a single element, normally present at that site, which develops and grows at virtually the same rate as normal components, and is not likely to result in compression of the adjacent tissue (in contrast to neoplastic tissue).” A choristoma is defined as a “mass formed by maldevelopment of tissue of a type not normally found at that site.” Phacoma is defined as “a hamartoma found in phacomatosis,” a group of hereditary diseases characterized by hamartomas of multiple tissues. A nevus is a “birthmark; a circumscribed malformation of the skin, especially if colored by hyperpigmentation or increased vascularity; it may be predominantly epidermal, adnexal, melanocytic, vascular, or mesodermal, or a localized overgrowth of melanin-forming cells arising in the skin early in life.” Ophthalmologists have adopted the term “nevi” to refer to developmental melanocytic lesions of the uveal tract, and it has been suggested as an appropriate term to describe developmental placoid lesions of the RPE. Developmental uveal melanocytic nevi have been described in Chapter 14 .
It is important to realize that reactive proliferation of RPE, retinal glial cells, and retinal vascular endothelial cells can occasionally duplicate the clinical and histopathologic changes of all of the RPE hamartomatous lesions discussed in this chapter.
Melanotic Nevi of the Retinal Pigment Epithelium
Solitary-Type Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
Solitary-type CHRPEs are well-demarcated, slightly elevated, gray-brown to black, oval, round, or occasionally geographic lesions with smooth or scalloped margins ( Figures 12.01–12.03 ). They are usually solitary but may be multiple and grouped in a pattern suggesting animal tracks ( Figure 12.01 A). A CHRPE may occur anywhere in the fundus. However, CHRPE in macula and juxtapapillary location are rare. There is often a halo of depigmentation just inside the outer edge of these lesions ( Figure 12.01 E and F). Although most CHRPE are between one and two disc diameters, some may occupy an area equal to one quadrant of the fundus ( Figure 12.01 B). They have been observed in newborns. Hypopigmented or depigmented lacunae within these lesions are frequently evident, particularly in older patients ( Figures 12.01 B, D, E, and I, and 12.03 G and H). These lacunae may show progressive enlargement, and eventually the entire lesion may become depigmented ( Figure 12.01 G). Although most of these lesions remain rather stationary, concentric enlargement has been demonstrated in up to 74–83% of cases ( Figure 12.01 H and I). Occasionally, linear depigmented streaks and localized zones of mild hyperpigmentation occur at the anterior margin of these lesions. Uncommonly, nodular growth may develop within CHRPE with histological confirmation of malignant transformation into adenocarcinoma of the RPE.
Many CHRPE are associated with either a relative or an absolute scotoma corresponding to the site of the lesion. CHRPE are hypoautofluorescent exhibiting mild hyper-autofluoresence of the lacunae. Fluorescein angiography in patients with lightly pigmented fundi shows obstruction of the background choroidal fluorescence in the area of the lesion except in the fenestrated areas of hypopigmentation ( Figure 12.01 C). Angiographic evidence of alterations in the structure and permeability of the retinal vessels overlying these lesions may occasionally occur. This includes capillary nonperfusion, capillary leakage, and chorioretinal anastomosis. Optical coherence tomography (OCT) reveals thinning of overlying retina with overall thickening of RPE layer, except in the region of lacunae, where RPE thinning is expected ( Figure 12.02 I and J).
Histopathologically, CHRPE lesions are characterized by a single layer of enlarged RPE cells containing macromelanin granules that may be associated with varying degrees of degeneration of the overlying outer retinal layers ( Figure 12.02 ). Some degree of RPE hyperplasia may also be evident. Absence of lipofuscin in the hypertrophied RPE cells suggests that their incapacity to phagocytose and digest photoreceptor outer segments may be responsible for the receptor cell degeneration so often present overlying these lesions. This may explain the thinning of the overlying neurosensory retina seen on OCT ( Figure 12.02 I and J). The structure of the macromelanosomes in CHRPE is similar to that described in X-linked ocular albinism.
The differential diagnosis of CHRPE includes choroidal melanocytic nevi, secondary and primary hyperplasia of the RPE, pigmented hypertrophic chorioretinal scars, and geographic dark fundus patches that are probably caused by subretinal bleeding and hemosiderin deposits, usually occurring in patients with sickle-cell disease (see Figures 6.59C and D and 6.58I). The large lesions, if not viewed binocularly, may be mistaken for malignant melanomas of the choroid ( Figure 12.01 B).
These lesions are similar histopathologically to lesions referred to as congenital grouped pigmentation of the RPE (see next subsection). Hypertrophy of the RPE has been identified histopathologically as being part of combined RPE and retinal hamartomas (see Figures 12.08 K and 12.10 E).
Multiple CHRPE Associated with Familial Adenomatous Polyposis and Gardner’s Syndrome
Multiple isolated CHRPE lesions occur usually in both eyes of a high percentage of patients with this dominantly inherited familial cancer syndrome that includes intestinal polyposis, osteomas of the skull, and various soft-tissue tumors, including fibromas, lipomas, and epidermal and sebaceous cysts. The risk for intestinal malignancy during adult life is virtually 100%. The soft-tissue tumors tend to occur during the first two decades, the bony tumors in the second decade, and the polyps in adulthood (mean age 30 years). Osteomas of the orbit may occur. Approximately 50% of patients will develop adenocarcinoma of the colon by 35 years of age. There is a disproportionate risk of other cancers (carcinoma of ampulla of Vater, adrenal gland, thyroid gland, and bladder), a variety of sarcomas, and neuroepithelial tumors (Turcot syndrome) ( Figure 12.03 G–I). Multiple CHRPE affecting both eyes is a reliable marker for Gardner’s syndrome. Multiple CHRPE appears to be specific for Gardner’s syndrome and is not found in the other familial intestinal polyposis syndromes (familial polyposis without extraintestinal manifestations, Peutz–Jeghers syndrome) or in patients with familial nonpolyposis colorectal cancers. The CHRPE lesions in Gardner’s syndrome often show a peculiar oval shape with a fishtail-like change at one or both poles ( Figure 12.03 C, E, and F). In some cases the lesions appear to be located in close approximation to the major retinal vessels and may be associated with abnormalities in the overlying retinal vessels. Histopathologically, some of the lesions appear similar to solitary CHRPE. Others show in addition hamartomatous malformations of the RPE featuring cellular hypertrophy, hyperplasia, and retinal invasion, and formation of a mushroom-shaped tumor ( Figure 12.03 K and L).
Patients with bilateral lesions, multiple lesions (more than 4), or both are specific (specificity, 0.95) and sensitive (sensitivity, 0.78) markers for Gardner’s syndrome. A review of published studies regarding genotype–phenotype correlation suggests that CHRPE is associated with mutations between codons 311 and 1444 of the adenomatous polyposis coli (APC) gene. The gene for adenomatous polyposis of the colon ( APC ) was found to be on 5q21-22 by Bodmer et al. There is no evidence that typical solitary or grouped CHRPE lesions represent a marker for Gardner’s syndrome. Multifocal CHRPE lesions have occurred in a family with microcephaly and hyperreflexia and in one family in Miami without any other abnormalities ( Figure 12.03 ).
Grouped-Type Congenital Pigmented Nevi of the Retinal Pigment Epithelium, “Bear Tracks”
This is a rare congenital anomaly first described in 1868 by Mauthner. It is characterized by sharply circumscribed, small, variably sized, pigment spots that are often arranged in groups to resemble the footprints of animals ( Figure 12.04 ). They are usually grouped in one sector of the fundus with the smaller spots located at the apex directed toward the optic disc. They infrequently are present in the macular area. Extensive areas of the fundus may be affected and be associated with bilateral involvement ( Figure 12.04 D and E). The lesions can occasionally be quite large and simulate “elephant tracks or grizzly bear tracks” ( Figure 12.04 H–L), a finding that has been noted as early as 1926. Familial cases involving two successive generations are reported. Two sisters, one with pigmented bear tracks and the other with albinotic spots, have been seen. Whether the grouped pigmentation and the other associations in a patient with microcephaly, mild mental retardation, and deletions of 13q33.3-q34 and 11p15.4 are causally related cannot be established. The retina overlying “bear tracks” appears normal bio-microscopically and angiographically. Electro-oculographic findings are normal. These lesions are believed to be stationary, but long-term follow-up studies have not been done. Grouped nevi have infrequently occurred in association with other anomalies or disorders including retinoblastoma and skin hyperpigmentation.
These lesions histopathologically are similar to CHRPE with increased number of pigment granules in normal-sized RPE cells. Unlike CHRPE most of the melanin granules retain their ellipsoidal shape and hypertrophy and hyperplasia of the RPE are less prominent. Clinically, some patients may show lesions typical of both grouped nevi and CHRPE ( Figures 12.01 A and 12.04 G).
Albinotic and Nonpigmented Nevi of the Retinal Pigment Epithelium
Grouped-Type Congenital Albinotic and Hypomelanotic Nevi of the Retinal Pigment Epithelium, “Polar Bear Tracks”
Congenital grouped albinotic nevi are multiple, white, variably sized spots involving the RPE in a pattern similar to that in congenital grouped pigmentation of the RPE ( Figure 12.05 ). They may occur in one or both eyes and may be mistaken for other flecked retina diseases (e.g., drusen, fundus flavimaculatus, pattern dystrophy, fundus albipunctatus, and Gaucher’s disease). Like pigmented “bear tracks,” these albinotic spots occur rarely and tend to be more numerous and larger in the peripheral fundus, and they usually do not involve the macular area. They appear to represent focal thickening of the RPE that is filled with a white material. This white material may be diffusely distributed or may be more concentrated in the periphery of the lesion ( Figure 12.05 A and C). In some cases the spots appear to be devoid of white material, and the underlying choroidal vessels are visible. In other cases, some of the spots may appear to contain dark gray pigment. The overlying retina appears normal, except that larger retinal vessels may appear to be locally narrowed ( Figure 12.05 C and D). The lesions are probably relatively stable, but further long-term follow-up studies are required to document this. Although considered to be functionally of no significance, one patient with macular as well as peripheral lesions developed neovascularization ( Figure 12.05 G and H).
Fluorescein angiography shows variable degrees of transmission of the choroidal fluorescence through these lesions ( Figure 12.05 B).
Although longer follow-up of these rarely encountered patients is required, it is probable that the albinotic spots represent a congenital anomaly of the RPE closely akin to congenital grouped hyperpigmentation of the RPE. In the case of the albinotic spots, the RPE cells appear to be stuffed with a white material, possibly an abnormal precursor of melanin rather than enlarged melanin granules as in grouped hyperpigmentation of the RPE.
Dr. Gass believed that these albinotic RPE spots are identical to those reported by Kandori and associates in association with stationary night blindness that was manifest primarily by abnormal dark adaptation. None of the four patients seen at the Bascom Palmer Eye Institute had nyctalopia. Studies, including dark adaptation, electroretinography, and electro-oculography, were normal in the two patients illustrated in Figure 12.05 A–C, G, and H. Parke et al. reported similar white spots in one of two siblings with pigmented RPE lesions, microcephaly, mental retardation, and autosomal-dominant hyperreflexia.
Solitary-Type Hypomelanotic and Albinotic Nevi (Torpedo Maculopathy)
These solitary, sharply circumscribed, hypopigmented reddish-orange or white lesions of the RPE, which have been previously referred to as “congenital hypomelanotic freckle” or “retinal albinotic spots,” are most frequently observed in the peripheral fundus and in the temporal half of the macula. These latter lesions often have an oval or fish-shaped appearance similar to that seen in the CHRPE lesions associated with Gardner’s syndrome ( Figure 12.06 A and D–F). They are often discovered on routine eye examination in children. They may or may not be associated with a demonstrable visual field defect. Although they may show a slight milky white color, they are rarely as densely white as the grouped albinotic RPE nevi. Unlike most acquired atrophic lesions of the RPE, hypopigmented RPE nevi typically have no margin or irregular hyperpigmentation. Angiographically the chorio-capillaris underlying these lesions appears to be normal ( Figure 12.06 B and C). OCT done on two patients by Golchet et al. has shown thin RPE with increased signal transmission in the choroid. Both patients showed a “cleft” in the outer retina associated with loss of photoreceptors, irregular edges of the residual photoreceptors, and thinning of the outer plexiform layer. The OCT finding remained unchanged over 6 years of follow-up in one patient. The authors inferred that “something occupied the cleft, the nature of which is unknown.” It is likely that this space is empty due to loss of the overlying photoreceptors; both patients had an absolute scotoma corresponding to the lesion. The OCT appearance has led to speculation that the lesion may not be a nevus, but rather a localized congenital thin or atrophic RPE.
Why this bears the same shape as a torpedo or fish-shaped CHRPE ( Figure 12.03 A–F) as seen in patients with intestinal polyposis (Gardner’s) is unclear, if it indeed is not a CHRPE. It is likely the same trigger causes the lesions in both these conditions, but the pigment epithelium is devoid of melanosomes here while the Gardner’s eyes develop an excess of them. Choroidal neovascularization arising at the edge of a lesion is rare but reported ( Figure 12.06 J–L). Microscopically, hypopigmented RPE nevi show a sharp transition from normal RPE to flat nonpigmented epithelium ( Figure 12.06 G and H). Unlike the presentation in most cases of congenital hypertrophy of the RPE, the overlying retina is normal. The underlying choroid is also unaffected. So far there are no histopathologic studies of solitary nevi that clinically appear white.
Congenital Simple Hamartoma of the Retinal Pigment Epithelium (Congenital Hyperplasia of the Retinal Pigment Epithelium, Pigment Epithelial Adenoma)
Children as well as adults with focal, solitary, nodular, black subretinal lesions that extend anteriorly into and usually through the entire thickness of the retina that probably are hamartomas composed of hyperplastic RPE have been observed ( Figure 12.07 ). The hamartomas are associated with minimal dilatation of the feeding and draining retinal vessels, retinal exudation, surrounding retinal traction, and pigmented vitreous cells ( Figure 12.07 A). Like solitary hypomelanotic RPE nevi, these lesions are frequently discovered in the temporal macular area of normal children or young adults on routine eye examination. Fluorescein angiography reveals that these lesions are nonfluorescent early but may show evidence of some staining late or a slight halo of fluorescence at the border ( Figure 12.07 B and C). The lesions are echodense on B-scan and display high internal reflectivity on A-scan. Three patterns of retinal involvement have been illustrated by Gass: superficial involvement in the retina, full-thickness retinal involvement with preretinal extension and full-thickness involvement with intrinsic vascularization ( Figure 12.07 G).
To date no change in the size of these lesions has been documented. Some of the large pigment epithelial adenomas in eyes enucleated because of suspected choroidal melanomas probably are also of developmental origin.
Combined Pigment Epithelial and Retinal Hamartoma
Combined pigment epithelial and retinal hamartomas are peculiar, slightly elevated, partly pigmented lesions, which may be mistaken for a postinflammatory scar or a malignant melanoma, and which may be present anywhere in the fundus. The clinical history, appearance of the tumor, and its structure vary with its location.
Combined Pigment Epithelial and Retinal Hamartoma Involving the Optic Disc
Patients with tumors that involve the optic nerve head and juxtapapillary retina typically are seen in young adults because of blurred and distorted vision in one eye. The visual acuity is usually 20/100 or better. Biomicroscopic examination reveals an ill-defined, slightly elevated, partly pigmented tumor involving part of the optic nerve head and adjacent retina ( Figure 12.08 ). The tumor is composed of a fine granular distribution of pigment, giving it a charcoal-gray filigree appearance. The presence of many fine capillaries within the tumor may be partly obscured from view by a semitranslucent gray membrane that is always present on the inner retinal surface. Patients become symptomatic either because of metamorphopsia caused by contraction of this membrane that produces traction folds in the retina that extend into the central macular area ( Figure 12.08 A), or less frequently because of subretinal and intraretinal exudation derived from the capillary component of the tumor ( Figure 12.08 D). This exudation may reabsorb spontaneously and leave atrophic changes in the RPE surrounding the tumor. Other complications that may occur infrequently include choroidal neovascularization, retinal hemorrhages, and vitreous hemorrhages. The early phases of angiography demonstrate dilated, multiple, fine blood vessels within the tumor, and later phases show evidence of leakage of dye from these vessels ( Figure 12.08 B, C, E, F, H, and I). The clinical appearance and fluorescein angiogram features are enough to make the diagnosis in most cases. OCT is useful in distinguishing lesions that are not very thick from epiretinal membranes by detecting disorganized underlying retina. Vitreous traction if present may also be detected, and thus help in selecting cases that may have a potential for visual improvement with vitrectomy and membrane peel to relieve traction.
