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Adenocarcinoma Arising From Congenital Hypertrophy of Retinal Pigment Epithelium
Jerry A. Shields, MD;
Carol L. Shields, MD;
Ralph C. Eagle, Jr, MD;
Arun D. Singh, MD
Arch Ophthalmol. 2001;119:597-602.
ABSTRACT
Congenital hypertrophy of the retinal pigment epithelium (CHRPE), traditionally
regarded as a benign stationary condition, has recently been shown in 5 cases
to give rise to an elevated, solid tumor. However, the histopathologic nature
of the tumor that arises from CHRPE has not been previously determined. A
65-year-old woman developed a progressively enlarging peripheral fundus tumor
that arose from a focus of classic CHRPE. The tumor produced a localized exudative
retinal detachment, cystoid macular edema, and surface-wrinkling retinopathy.
The mass was removed by local resection, and histopathologic examination revealed
a low-grade adenocarcinoma of the retinal pigment epithelium, apparently arising
from CHRPE. Although CHRPE is usually a benign nonprogressive lesion, it can
give rise to a malignant tumor. Congenital hypertrophy of the retinal pigment
epithelium should be observed periodically for development of a neoplasm.
INTRODUCTION
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is
a well-known fundus abnormality that generally occurs as an asymptomatic flat
lesion at the level of the retinal pigment epithelium (RPE).1-7
It can appear as a solitary condition1-2,8-10
or as multifocal lesions known as congenital grouped pigmentation or "bear
tracks." Although the solitary and the multifocal forms were once believed
to be stationary lesions, there have been reports of solitary CHRPE that showed
minimal increase in diameter.11-15
We recently reported 5 cases of CHRPE, each of which spawned a slowly
enlarging, elevated mass that we presumed to be a neoplasm of the RPE.16 At the time of that report, there was no available
histopathologic diagnosis for any of the tumors. However, in one of those
patients, the tumor recently showed enlargement, caused visual loss, and was
removed by an eye-wall resection. We report the findings on that tumor, which
proved to be a low-grade adenocarcinoma that apparently arose from CHRPE.
REPORT OF A CASE
In January 1997, a 63-year-old woman with a 2-year history of slightly
blurred vision in the right eye was found to have an ipsilateral fundus mass.
She was referred to the Oncology Service at Wills Eye Hospital for management
of a possible choroidal melanoma. She had undergone mastectomy for breast
cancer 14 years earlier, with no local or systemic recurrence.
Her unaffected left eye had a visual acuity of 20/20 and was entirely
normal. Her right eye had a visual acuity of 20/40 and normal intraocular
pressure. Slitlamp biomicroscopy demonstrated a small, central posterior subcapsular
cataract, and trace flare and trace cells in the anterior vitreous cavity.
Fundus examination of the right eye disclosed a 12 x 10-mm, flat area
of black pigmentation located between the ora serrata and the equator superiorly.
It had a well-defined margin, scalloped border, and depigmented lacunae—characteristics
of CHRPE. Arising abruptly from within the CHRPE was an amelanotic mass measuring
7 x 7 x 3 mm that was supplied and drained by slightly dilated
retinal blood vessels (Figure 1).
The mass appeared to involve full-thickness retina, lack intrinsic pigmentation,
and contain fine corkscrew vessels. Sparse vitreous cells were evident above
the mass, and surface-wrinkling retinopathy with mild cystoid macular edema
accounted for the patient's vision loss.
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Figure 1. A, Fundus drawing in January 1997
showing a fleshy yellow mass arising in area of congenital hypertrophy of
the retinal pigment epithelium. B, Fundus photograph in January 1997.
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Transcleral transillumination showed a moderate shadow measuring 12
x 10 mm in diameter, corresponding to the area of CHRPE. Within that
shadow was a darker, distinct shadow measuring 7 x 7 mm, corresponding
to the nodule seen clinically. With fluorescein angiography, the mass showed
early hyperfluorescence and late staining, with leakage of fluorescein dye
into the adjacent vitreous cavity (Figure
2). B-scan ultrasonography revealed a solid, dome-shaped mass that
measured 3.0 mm in thickness (Figure 3A).
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Figure 2. A, Fluorescein angiogram in venous
phase showing retinal feeder vessels and hyperfluorescent mass superiorly.
The frames in the arterial phase clearly showing filling through retinal blood
vessels are not available. B, Late-phase fluorescein angiogram showing hyperfluorescent
mass with leakage of fluorescein in the overlying vitreous.
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Figure 3. A, B-scan ultrasonogram in January
1997 showing elevated mass with medium-low internal reflectivity. B, B-scan
ultrasonogram taken 30 months later showing enlargement of the mass and higher
internal reflectivity in the tumor.
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Our initial differential diagnoses included retinal vasoproliferative
tumor17-18 and neoplasm of the
pigment epithelium.19-20 Choroidal
melanoma and metastasis were believed to be less likely.
It was decided that we observe the lesion at 6-month intervals. During
the next 36 months, the mass gradually enlarged in thickness (Figure 3B) and diameter (Figure
4), the visual acuity slowly worsened, the retinal feeder vessels
became more dilated, and localized retinal exudation and secondary retinal
detachment developed. The surface-wrinkling retinopathy and cystoid foveal
edema became more pronounced. In addition, the smooth surface of the tumor
disappeared because the tumor cells were diffusely infiltrating the overlying
vitreous. Ultrasonography revealed that the thickness of the mass increased
to 4.5 mm (Figure 3B).
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Figure 4. A, Fundus drawing in late 1999
showing a fleshy yellow mass arising in the area of CHRPE and invading the
overlying vitreous, producing subretinal exudation. B, Fundus photograph taken
at the same time as Figure 4A. Note that the tumor has enlarged in diameter
and thickness and is producing subretinal exudation.
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The patient was informed that the enlarging tumor was likely to cause
further vision loss secondary to vitreal seeding, retinal detachment, surface-wrinkling
retinopathy, and vitreous hemorrhage. The options of diagnostic fine-needle
aspiration biopsy, cryotherapy, irradiation, and tumor removal were discussed,
and the patient elected to have tumor removal. After prophylactic laser photocoagulation
posterior to the mass, the tumor was removed by a modified eye-wall resection.21 Postoperatively, the patient developed peripheral
hemorrhagic retinal detachment and underwent pars plana vitrectomy, air/fluid
exchange, vitreous instillation of sulfur hexafluoride gas, and cryotherapy.
In February 2000, visual acuity was 20/400, and the retina was flat. There
was pigment mottling in the fovea, and the area of the original tumor appeared
as a flat yellow scar.
PATHOLOGICAL FEATURES
The specimen was fixed in formaldehyde and submitted for routine processing.
Gross inspection showed an ovoid mass with a thin strip of sclera at its base.
The superficial portion of the tumor was nonpigmented, and the deeper portion
was pigmented. Microscopic examination revealed a segment of choroid and a
partially pigmented moundlike tumor that rested on the denuded inner surface
of Bruch's membrane. The sensory retina and the choroid were infiltrated with
amelanotic tumor cells (Figure 5).
The pigmented cells were arranged in a tubuloacinar configuration and contained
large round melanosomes. The more superficial portion of the tumor that replaced
the retina was composed of similar epithelial cells, except that they had
minimal cytoplasmic pigmentation (Figure 6). Some of the nuclei contained prominent nucleoli, and rare mitotic
figures were identified. The apical part of the neoplasm directly invaded
the vitreous cavity, where it was topped by a layer of fibrinous exudate.
There was extensive choroidal invasion by sheets and tongues of similar amelanotic
tumor cells. Conspicuous foci of chronic inflammatory cells, including mature
plasma cells with scattered Russell bodies, were present within the tumor
and the underlying choroid. In some areas, the tumor cells formed cords and
bands that rested on prominent periodic acid-Schiff–positive connective
tissue septa, most likely representing basement membrane (Figure 7). Short segments of tall, heavily pigmented RPE cells consistent
with residual CHRPE were present on Bruch's membrane at the base of the tumor
(Figure 8).
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Figure 5. Low-magnification photomicrograph
of the tumor showing junction between basal pigmented cells and more superficial
nonpigmented cells. The tumor has diffusely replaced the choroid (below) and
the sensory retina (above) (hematoxylin-eosin, original magnification x15).
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Figure 6. Large amelanotic epithelial cells
with nuclear pleomorphism located in the retina. Similar cells invaded the
underlying choroid. One mitotic figure is evident (hematoxylin-eosin, original
magnification x250).
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Figure 7. Section through the central portion
of the tumor showing solid cords of epithelial cells that rest on septae of
prominent basement membrane (periodic acid–Schiff, original magnification
x250).
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Figure 8. Monolayer of deeply pigmented
epithelial cells consistent with congenital hypertrophy of the retinal pigment
epithelium near the base of the tumor. Note the abrupt transition between
the congenital hypertrophy of the retinal pigment epithelium and the overlying
mass (hematoxylin-eosin, original magnification x250).
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The tumor cells showed moderately intense immunoreactivity for vimentin,
moderate diffuse and focally intense immunoreactivity for cytokeratin marker
CAM 5.2, and trace to mild diffuse immunoreactivity for S100 protein. Scattered
tumor cells showed intense immunoreactivity for cytokeratin marker AE1. Melanoma-specific
antigen HMB-45 was nonreactive.
The tumor was classified as a low-grade adenocarcinoma of the RPE based
on the local invasion of the choroid, retina, and vitreous, and the presence
of nuclear pleomorphism with prominent nucleoli and occasional mitotic figures.
The final diagnosis was low-grade adenocarcinoma arising from CHRPE.
COMMENT
Until recently, CHRPE was generally considered to be a stationary lesion
with no known tendency to enlarge or spawn solid neoplasms. In recent years,
however, solitary CHRPE has been observed on several occasions to increase
in basal dimensions,11-15
and histopathologic studies have shown evidence of associated RPE hyperplasia
in CHRPE lesions.7, 15 Our group
recently reported clinical observations on 5 cases of elevated, solid tumors
that apparently arose from typical CHRPE.16
From our observations on those 5 cases, it seems that tumors arising from
CHRPE slowly enlarge, invade the sensory retina, and develop a retinal blood
supply. Eventually, they can cause intraretinal exudation, which can lead
to an exudative retinal detachment, similar to that seen with retinal capillary
hemangioma and Coats disease. Preretinal macular fibrosis and cystoid foveal
edema are also common complications.
We believe that the tumors that arise from CHRPE have clinical and histopathological
features similar to other neoplasms of the pigment epithelium.19-20
Such tumors are usually dark gray to black, invade the sensory retina, acquire
a retinal blood supply, and produce exudative retinopathy.20
Although they are usually located in the peripheral fundus, they are frequently
associated with preretinal gliosis and cystoid edema in the macular area.
Based on our clinical observations of 5 cases and the histopathologic findings
on the 1 case reported here, it seems that true neoplasms of the RPE can arise
from CHRPE. In our case, the tumor proved histopathologically to be a low-grade
adenocarcinoma of the RPE arising from a focus of CHRPE.
Even though the tumor in our patient arose from the CHRPE, it appeared
clinically to be amelanotic. However, the deeper part of the tumor was pigmented
histopathologically. This finding accounted for the dark shadow produced by
transillumination of the seemingly amelanotic tumor. It seems that as these
tumors proliferate, some of them lose pigmentation. We have seen another case
of histopathologically proven adenocarcinoma of the RPE that was nonpigmented.22 In that case, the lesion presumably arose from a
juxtapapillary hyperplasia of the RPE in an eye with ocular histoplasmosis.22
The pathogenesis of the tumor described here is uncertain. Tumors of
the RPE may occur as reactive hyperplasia, benign adenoma, or malignant adenocarcinoma.
It is tempting to speculate that other reported neoplasms of the RPE may have
originated from foci of CHRPE, which underwent reactive hyperplasia and subsequent
neoplasia.20 However, the stimulus for such
change remains unknown. In a sense, such transformation of CHRPE into a neoplasm
of the RPE may be analogous to the malignant transformation of a choroidal
nevus into a malignant melanoma.
The diagnosis of an RPE neoplasm arising from CHRPE is best made by
indirect ophthalmoscopy with recognition of a pigmented or nonpigmented mass
arising from typical CHRPE with minimally dilated retinal feeding and draining
blood vessels. It is possible that such tumors may clinically obscure the
underlying CHRPE. If so, clinically the lesion is like other RPE tumors reported
in the literature.20 Fluorescein angiography
generally accentuates the feeder vessels and shows moderately intense hyperfluorescence
of the mass. Ultrasonography shows an abruptly elevated mass with medium to
high internal reflectivity, but the ultrasonographic findings alone may be
insufficient to consistently differentiate a neoplasm of the RPE from choroidal
melanoma.
The management of neoplasms arising from CHRPE should be similar to
that of other tumors of the RPE.20 The ultimate
treatment has not yet been determined, but it seems advisable to do fundus
photography and examine the lesion periodically if it is small and asymptomatic.
The other 4 patients we previously reported are currently being managed by
observation only. However, the patient reported here required active treatment
because the tumor was enlarging and was producing vision-threatening complications.
Although the best treatment for symptomatic cases is unknown, options include
treating the macular edema medically or with grid laser photocoagulation,
or treating the tumor with laser photocoagulation, cryotherapy, plaque brachytherapy,
or local resection. Local resection was performed in our patient with the
hope that removing the tumor completely would stabilize the progressive complications.
The visual prognosis varies for patients with neoplasms arising from
CHRPE. Most tumors are relatively small and show little change in the early
stages. With time, however, there is slow enlargement of the mass and progressive
exudative retinopathy, often with preretinal macular gliosis and cystoid macular
edema causing visual loss. The systemic prognosis is excellent. To our knowledge,
no adenocarcinoma of the RPE has exhibited distant metastasis.
In summary, we have documented a progressive, low-grade adenocarcinoma
that appeared clinically and histopathologically to arise from CHRPE. We recommend
that patients with CHRPE be followed up periodically for evolution of the
lesion into a neoplasm.
AUTHOR INFORMATION
Accepted for publication September 8, 2000.
This research was supported by the Eye Tumor Research Foundation, Philadelphia,
Pa; the Award of Merit in Retina Research, Houston, Tex (Dr J. Shields); the
Macula Foundation, New York, NY (Dr C. Shields); and the Noel T. and Sara
L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital (Dr Eagle).
Presented at the Annual Wills Eye Hospital Retina Club meeting, Philadelphia,
Pa, September 15, 2000, and at the Fluorescein Club, American Academy of Ophthalmology
Meeting, Dallas, Tex, October 22, 2000.
The authors acknowledge Eric Gurwin, MD, Steven Cohen, MD, and Carl
Regillo, MD, for their assistance in the care of this patient, and Ramon Font,
MD, for confirming the histopathologic diagnosis in consultation.
Corresponding author and reprints: Jerry A. Shields, MD, Oncology
Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.
From the Oncology Service (Drs J. Shields, C. Shields, and Singh),
Pathology Department (Dr Eagle), Wills Eye Hospital, Thomas Jefferson University,
Philadelphia, Pa.
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ABSTRACT
SECTION EDITOR: W. RICHARD GREEN, MD
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