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Malignant Transformation of Congenital Hypertrophy of the Retinal Pigment Epithelium
Malignant Transformation of Congenital Hypertrophy of the Retinal Pigment Epithelium Jerry A. Shields, MD,1 Ralph C. Eagle, Jr, MD,2 Carol L. Shields, MD,1 Gary C. Brown, MD,3 Sara E. Lally, MD1 Purpose: To report a clinicopathologic correlation of an adenocarcinoma that arose from solitary congenital hypertrophy of the retinal pigment epithelium (CHRPE). Design: Case report with clinicopathologic correlation. Methods: A 56-year-old black woman was referred for an asymptomatic fundus lesion in her left eye. It had features typical of CHRPE, but there was a small elevated nodule within the flat component, and the diagnosis was adenoma of the retinal pigment epithelium (RPE) arising from CHRPE. The lesion was observed periodically. The nodule slowly enlarged, and increasing amounts of lipoproteinaceous exudation accumulated in the adjacent retina. Thirteen years after the initial diagnosis, the patient returned with severe visual loss and no view of the fundus resulting from cataract and posterior synechia. Ultrasonography revealed a total retinal detachment and a pedunculated tumor measuring 7.5 mm in thickness. The eye was enucleated and studied histopathologically. Main Outcome Measures: Clinical evaluation and correlation of clinical findings with histopathologic results of the enucleated eye. Results: Histopathologically, the mass was composed of a proliferation of atypical RPE cells with a marked infiltration of benign plasma cells. Typical features of CHRPE were present at the base of the tumor. The final diagnosis was adenocarcinoma arising from CHRPE. Conclusions: Congenital hypertrophy of the retinal pigment epithelium, once considered to be a benign and stationary lesion, may spawn a malignant neoplasm. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:2213–2216 © 2009 by the American Academy of Ophthalmology.
Solitary congenital hypertrophy of the retinal pigment epithelium (CHRPE) typically is a flat, pigmented fundus lesion that was once believed to be stationary, with no potential to grow or to undergo malignant transformation.1 More recently, however, CHRPE has been recognized to enlarge slowly in diameter in 75% to 80% of cases.2,3 In addition to growth in diameter, CHRPE also has been recognized to spawn an elevated nodule, as documented in a report of 5 such cases.4 The exact nature of this elevated component was not known, but it was suspected to be a neoplasm of the RPE arising from CHRPE.5 This suspicion recently was confirmed in 2 histopathologic reports of low-grade adenocarcinoma of the RPE arising from CHRPE.5,6 Herein is a report of a clinicopathologic correlation of a neoplasm arising from CHRPE that proved histopathologically to be a malignant adenocarcinoma. Institutional review board approval for publication was obtained from Wills Eye Institute of Thomas Jefferson University.
Case Report In 1995, a 56-year-old black woman was referred for an asymptomatic pigmented fundus lesion in her left eye, suspected to be a choroidal melanoma. It had features typical of CHRPE, but there was a small nodule in the lesion with adjacent yellow retinal © 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
exudation (Fig 1A) that measured 1.5 mm thick on ultrasonography (Fig 1B). The diagnosis was adenoma of the RPE arising from CHRPE. The lesion was observed yearly until 1998, when the nodule showed minimal enlargement and the vision remained 6/6. Yearly follow-up was recommended. When she next returned in 2003, she had decreased vision (6/30), the elevated mass was larger, and there was more intraretinal and subretinal lipoproteinaceous exudation (Fig 1C). There were signs of intraocular inflammation with fibrin-like material in the anterior chamber and early posterior synechiae. Options of observation, laser treatment, cryotherapy, local tumor resection, and irradiation were discussed, but the patient declined any active treatment. In March 2008, 13 years after initial diagnosis, she returned with a visual acuity of hand movements, and there was no view of the fundus because of advanced cataract and posterior synechia. B-scan ultrasonography demonstrated a pedunculated tumor 7.5 mm in thickness and extensive shallow retinal detachment (Fig 1D). The clinical diagnosis was adenocarcinoma of the retinal pigment epithelium (RPE) arising from CHRPE; melanoma was considered to be unlikely. Because of the possibility of malignant transformation of CHRPE and the poor visual prognosis, the patient elected to undergo enucleation.
Pathologic Analysis Gross examination of the sectioned globe disclosed a pedunculated, pigmented mass measuring 8 mm in basal diameter and 6 mm in thickness that arose from the RPE in the equatorial region. ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2009.04.048
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Ophthalmology Volume 116, Number 11, November 2009
Figure 1. Images showing progressive clinical course of the lesion. A, Fundus photograph of lesion as seen in 1995 showing congenital hypertrophy of retinal pigment epithelium near the equator supranasally in left eye. Note the small nodule and the adjacent yellow retinal exudation. B, B-scan ultrasonogram of lesion as seen in 1995 showing minimal elevation of the nodule. C, Fundus photograph of same lesion as seen in 2003. The elevated nodule has enlarged and there is more exudation. Ultrasound (not shown) demonstrated increased thickness of the tumor. D, B-scan ultrasonogram of lesion as seen in 2008 showing marked enlargement of the lesion, which appears to have a pedunculated configuration.
The tumor had eroded through the retina and was surrounded by an extensive, shallow, exudative retinal detachment. Parts of the adjoining retina and subretinal space contained foci of densely yellow material. The surface of the tumor was pigmented and its deeper portions were nonpigmented (Fig 2A, B). Histopathologic analysis disclosed a dome-shaped neoplasm arising from the RPE that rested on the inner surface of the Bruch membrane and was surrounded by an extensive, shallow retinal detachment with eosinophilic subretinal fluid. Although its surface was pigmented heavily, much of the tumor was composed of relatively nonpigmented cells with round to oval nuclei with prominent nucleoli. Several clones of atypical RPE cells that varied in cytologic features and pigment content were present. In some areas, the cells formed characteristic linear arrays and bands that rested on septa that showed positive results for periodic acid–Schiff. The cells comprising approximately one fourth of the tumor were somewhat better differentiated and arranged in a papillary pattern (Fig 2C). Another area was composed of poorly differentiated, less pigmented cells (Fig 2D). Three mitoses, including an atypical mitotic figure, were counted in 40 high-power fields. A segment of intensely pigmented RPE consistent with residual CHRPE was identified at the base of the tumor posteriorly (Fig 2E). Prominent infiltrates of plasma cells were present on the surface and within the substance of the tumor (Fig 2F). The inflammatory infiltrate contained numerous Russell bodies, including unusual square forms. A battery of immunohistochemical stains was performed. The tumor cells showed varying degrees of positive immunoreactivity for cytokeratin markers cytokeratin (CK7), AE1/AE3, and CAM 5.2. A few foci of cells showed positive results for S-100 protein,
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but results for melanocytic markers Melan A and microphthalmic transcription factor (MITF) were negative. Cells in the more differentiated papillary part of the tumor also stained for vimentin. The KI-67 proliferation marker disclosed scattered cycling cells in the tumor. The final diagnosis was RPE adenocarcinoma arising from CHRPE. The tumor was classified as malignant based on cellular atypia, nuclear pleomorphism, and mitotic activity including atypical mitoses.
Discussion For many years, solitary CHRPE generally was believed to be a stationary lesion. However, it is now recognized that solitary CHRPE can show increase in basal dimensions, with one study of 64 cases finding basal enlargement in 74%2 and another report of 330 cases showing basal growth in 83%.3 These 2 series cite several other individual reports of horizontal enlargement of CHRPE.2,3 Furthermore, CHRPE also has been reported in a series of 5 cases to spawn an elevated nodule that can enlarge slowly, can invade the sensory retina, and can develop a retinal blood supply. When these small nodular lesions first were reported, their histopathologic features were unknown, but they were suspected to be either hyperplasia or a benign tumor (adenoma) of the RPE.4 In a case report in 2001, a progressively growing symptomatic tumor arising from CHRPE was removed by eye wall resection and was clas-
Shields et al 䡠 Malignant Transformation of CHRPE
Figure 2. Pathologic analysis results of the lesion after enucleation. A, Photograph showing gross appearance of the lesion with pigmented and nonpigmented components. B, Low-magnification photomicrograph of tumor (stain, hematoxylin– eosin; original magnification, ⫻10). C, Photomicrograph showing area of the tumor with papillary growth pattern corresponding to the right side of the tumor shown (panel C). The periodic acid–Schiff stain accentuates the basement membranes of the epithelial cells (arrow; stain, periodic acid–Schiff; original magnification, ⫻150). D, Photomicrograph showing area of more poorly differentiated tumor cells. Note the atypical mitotic figure (arrow). There is a linear infiltration of plasma cells adjacent to the mitotic figure (stain, hematoxylin– eosin; original magnification, ⫻400). E, Photomicrograph showing area of congenital hypertrophy of retinal pigment epithelium at the base of the tumor (arrow; stain, hematoxylin– eosin; original magnification, ⫻150). F, Photomicrograph showing marked infiltration of mature plasma cells in the tumor. Four Russell bodies are present just below the center of the image. Arrow depicts one Russell body (stain, hematoxylin– eosin; original magnification, ⫻300).
sified histopathologically as an adenocarcinoma.5 A similar case was reported in 2006 in which the tumor also was found to be a low-grade adenocarcinoma arising from CHRPE.6 In the case reported herein, the eye was enucleated because of progressive tumor growth, extensive retinal detachment, intraocular inflammation, and profound, irreversible visual loss. Thus, 3 malignant neoplasms arising from CHRPE are known, and it is likely that more cases have occurred but have not been diagnosed clinically because they generally are, small and asymptomatic and are found in the peripheral fundus, where they can remain undetected.
The nomenclature for acquired tumors of the RPE is confusing because various authors have used terms like adenoma and adenocarcinoma to describe the benign and malignant forms. Histopathologically, these tumors are composed of a proliferation of either benign or malignant RPE cells without glandular features. Hence, the terms benign epithelioma and malignant epithelioma may be preferable to adenoma and adenocarcinoma, respectively.1 Characteristic clinical features of primary tumors of the RPE, including those that originate from CHRPE, include the development of retinal blood vessels that supply and drain the tumor and yellow lipoproteinaceous retinal and
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Ophthalmology Volume 116, Number 11, November 2009 subretinal exudation.1,7 These findings should differentiate RPE tumors from choroidal melanoma, which rarely have feeder vessels or significant exudation. Ancillary studies also can assist in clinical diagnosis. Fluorescein angiography generally accentuates the feeder vessels and shows mild hyperfluorescence of the mass. Ultrasonography shows an abruptly elevated so-call derby hat–shaped mass with medium to high internal reflectivity. With time, these RPE tumors cause exudative retinal detachment, intraocular inflammation, vitreous traction, posterior synechiae, and cataract.7 Although such diffuse intraocular inflammation becomes progressively worse as the tumor enlarges, it is uncertain whether the tumor induces the secondary inflammation or whether the chronic inflammation promotes the growth of the tumor. The pathogenesis of the tumor described here is uncertain. It is tempting to speculate that other reported neoplasms of the RPE may have originated from foci of CHRPE and that the underlying CHRPE eventually was obscured by the overlying mass. An interesting aspect of the tumor reported here was the intense infiltration of the mass by plasma cells. A retrospective review of a previously reported case also showed the presence of many plasma cells.5 What stimulates the plasma cell infiltration of these tumors is uncertain. The best management of tumors arising from CHRPE has not been established. In a prior series of acquired RPE tumors without evidence of CHRPE, 2 tumors progressed to blindness and phthisis despite local irradiation.7 One other case in which a pigment epithelial tumor was associated with massive destruction of the eye is known.8 Enucleation was performed rather than irradiation because there was no hope for useful vision and the progressive growth suggested that the tumor was malignant. In retrospect, earlier treatment would have been advisable. The authors currently are following up several cases of small nodular tumors arising from CHRPE and have been hesitant to treat them because they are relatively small and asymptomatic and the vertical growth has been slow. In view of the now-recognized natural course of some of these lesions, however, it may be prudent to treat them when lipoproteinaceous exudation first appears and when the elevated lesion is still relatively small, even though the vision may be normal. It is not yet determined whether such treatment should be by laser, cryother-
apy, photodynamic therapy, local resection, or local irradiation, but each case should be individualized according to the clinical situation. To the authors’ knowledge, no malignant epithelioma (adenocarcinoma) of the RPE has exhibited distant metastases. In summary, the current case suggests that malignant neoplasms may arise from CHRPE. However, tumors of the RPE seem to have no potential to metastasize.1,8 Nevertheless, they can cause exudative retinal detachment and blindness. Therefore, earlier treatment, rather than prolonged observation, may be justified for progressive lesions. The ideal treatment of this intriguing neoplasm remains to be determined.
References 1. Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In: Shields JA, Shields CL, eds. Intraocular Tumors. An Atlas and Textbook. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2008:432– 83. 2. Chamot L, Zografos L, Klainguti G. Fundus changes associated with congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1993;115:154 – 61. 3. Shields CL, Mashayekhi A, Ho T, et al. Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features and frequency of enlargement in 330 patients. Ophthalmology 2003;110:1968 –76. 4. Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital hypertrophy of the retinal pigment epithelium. Arch Ophthalmol 2000;118:637– 41. 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. Trichopoulos N, Augsburger JJ, Schneider S. Adenocarcinoma arising from congenital hypertrophy of the retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 2006; 244:125– 8. 7. 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– 8. 8. Edelstein C, Shields CL, Shields JA, Eagle RC Jr. Presumed adenocarcinoma of the retinal pigment epithelium in a blind eye with a staphyloma. Arch Ophthalmol 1998;116:525– 8.
Footnotes and Financial Disclosures Originally received: December 8, 2008. Final revision: April 22, 2009. Accepted: April 24, 2009. Available online: September 10, 2009.
Manuscript no. 2008-1459.
1
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. 2
Department of Pathology, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
Supported by a donation from the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust (CLS), Philadelphia, Pennsylvania; the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); the LuEsther Mertz Retina Research Foundation (CLS); the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology (RCE), Philadelphia, Pennsylvania; and a donation from Michael, Bruce, and Ellen Ratner, New York, New York (CLS and JS).
3
Retina Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Correspondence: Jerry A. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: jerryshields@ comcast.net.
Solitary congenital hypertrophy of the retinal pigment epithelium (CHRPE) typically is a flat, pigmented fundus lesion that was once believed to be stationary, with no potential to grow or to undergo malignant transformation.1 More recently, however, CHRPE has been recognized to enlarge slowly in diameter in 75% to 80% of cases.2,3 In addition to growth in diameter, CHRPE also has been recognized to spawn an elevated nodule, as documented in a report of 5 such cases.4 The exact nature of this elevated component was not known, but it was suspected to be a neoplasm of the RPE arising from CHRPE.5 This suspicion recently was confirmed in 2 histopathologic reports of low-grade adenocarcinoma of the RPE arising from CHRPE.5,6 Herein is a report of a clinicopathologic correlation of a neoplasm arising from CHRPE that proved histopathologically to be a malignant adenocarcinoma. Institutional review board approval for publication was obtained from Wills Eye Institute of Thomas Jefferson University.
Case Report In 1995, a 56-year-old black woman was referred for an asymptomatic pigmented fundus lesion in her left eye, suspected to be a choroidal melanoma. It had features typical of CHRPE, but there was a small nodule in the lesion with adjacent yellow retinal © 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
exudation (Fig 1A) that measured 1.5 mm thick on ultrasonography (Fig 1B). The diagnosis was adenoma of the RPE arising from CHRPE. The lesion was observed yearly until 1998, when the nodule showed minimal enlargement and the vision remained 6/6. Yearly follow-up was recommended. When she next returned in 2003, she had decreased vision (6/30), the elevated mass was larger, and there was more intraretinal and subretinal lipoproteinaceous exudation (Fig 1C). There were signs of intraocular inflammation with fibrin-like material in the anterior chamber and early posterior synechiae. Options of observation, laser treatment, cryotherapy, local tumor resection, and irradiation were discussed, but the patient declined any active treatment. In March 2008, 13 years after initial diagnosis, she returned with a visual acuity of hand movements, and there was no view of the fundus because of advanced cataract and posterior synechia. B-scan ultrasonography demonstrated a pedunculated tumor 7.5 mm in thickness and extensive shallow retinal detachment (Fig 1D). The clinical diagnosis was adenocarcinoma of the retinal pigment epithelium (RPE) arising from CHRPE; melanoma was considered to be unlikely. Because of the possibility of malignant transformation of CHRPE and the poor visual prognosis, the patient elected to undergo enucleation.
Pathologic Analysis Gross examination of the sectioned globe disclosed a pedunculated, pigmented mass measuring 8 mm in basal diameter and 6 mm in thickness that arose from the RPE in the equatorial region. ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2009.04.048
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Ophthalmology Volume 116, Number 11, November 2009
Figure 1. Images showing progressive clinical course of the lesion. A, Fundus photograph of lesion as seen in 1995 showing congenital hypertrophy of retinal pigment epithelium near the equator supranasally in left eye. Note the small nodule and the adjacent yellow retinal exudation. B, B-scan ultrasonogram of lesion as seen in 1995 showing minimal elevation of the nodule. C, Fundus photograph of same lesion as seen in 2003. The elevated nodule has enlarged and there is more exudation. Ultrasound (not shown) demonstrated increased thickness of the tumor. D, B-scan ultrasonogram of lesion as seen in 2008 showing marked enlargement of the lesion, which appears to have a pedunculated configuration.
The tumor had eroded through the retina and was surrounded by an extensive, shallow, exudative retinal detachment. Parts of the adjoining retina and subretinal space contained foci of densely yellow material. The surface of the tumor was pigmented and its deeper portions were nonpigmented (Fig 2A, B). Histopathologic analysis disclosed a dome-shaped neoplasm arising from the RPE that rested on the inner surface of the Bruch membrane and was surrounded by an extensive, shallow retinal detachment with eosinophilic subretinal fluid. Although its surface was pigmented heavily, much of the tumor was composed of relatively nonpigmented cells with round to oval nuclei with prominent nucleoli. Several clones of atypical RPE cells that varied in cytologic features and pigment content were present. In some areas, the cells formed characteristic linear arrays and bands that rested on septa that showed positive results for periodic acid–Schiff. The cells comprising approximately one fourth of the tumor were somewhat better differentiated and arranged in a papillary pattern (Fig 2C). Another area was composed of poorly differentiated, less pigmented cells (Fig 2D). Three mitoses, including an atypical mitotic figure, were counted in 40 high-power fields. A segment of intensely pigmented RPE consistent with residual CHRPE was identified at the base of the tumor posteriorly (Fig 2E). Prominent infiltrates of plasma cells were present on the surface and within the substance of the tumor (Fig 2F). The inflammatory infiltrate contained numerous Russell bodies, including unusual square forms. A battery of immunohistochemical stains was performed. The tumor cells showed varying degrees of positive immunoreactivity for cytokeratin markers cytokeratin (CK7), AE1/AE3, and CAM 5.2. A few foci of cells showed positive results for S-100 protein,
2214
but results for melanocytic markers Melan A and microphthalmic transcription factor (MITF) were negative. Cells in the more differentiated papillary part of the tumor also stained for vimentin. The KI-67 proliferation marker disclosed scattered cycling cells in the tumor. The final diagnosis was RPE adenocarcinoma arising from CHRPE. The tumor was classified as malignant based on cellular atypia, nuclear pleomorphism, and mitotic activity including atypical mitoses.
Discussion For many years, solitary CHRPE generally was believed to be a stationary lesion. However, it is now recognized that solitary CHRPE can show increase in basal dimensions, with one study of 64 cases finding basal enlargement in 74%2 and another report of 330 cases showing basal growth in 83%.3 These 2 series cite several other individual reports of horizontal enlargement of CHRPE.2,3 Furthermore, CHRPE also has been reported in a series of 5 cases to spawn an elevated nodule that can enlarge slowly, can invade the sensory retina, and can develop a retinal blood supply. When these small nodular lesions first were reported, their histopathologic features were unknown, but they were suspected to be either hyperplasia or a benign tumor (adenoma) of the RPE.4 In a case report in 2001, a progressively growing symptomatic tumor arising from CHRPE was removed by eye wall resection and was clas-
Shields et al 䡠 Malignant Transformation of CHRPE
Figure 2. Pathologic analysis results of the lesion after enucleation. A, Photograph showing gross appearance of the lesion with pigmented and nonpigmented components. B, Low-magnification photomicrograph of tumor (stain, hematoxylin– eosin; original magnification, ⫻10). C, Photomicrograph showing area of the tumor with papillary growth pattern corresponding to the right side of the tumor shown (panel C). The periodic acid–Schiff stain accentuates the basement membranes of the epithelial cells (arrow; stain, periodic acid–Schiff; original magnification, ⫻150). D, Photomicrograph showing area of more poorly differentiated tumor cells. Note the atypical mitotic figure (arrow). There is a linear infiltration of plasma cells adjacent to the mitotic figure (stain, hematoxylin– eosin; original magnification, ⫻400). E, Photomicrograph showing area of congenital hypertrophy of retinal pigment epithelium at the base of the tumor (arrow; stain, hematoxylin– eosin; original magnification, ⫻150). F, Photomicrograph showing marked infiltration of mature plasma cells in the tumor. Four Russell bodies are present just below the center of the image. Arrow depicts one Russell body (stain, hematoxylin– eosin; original magnification, ⫻300).
sified histopathologically as an adenocarcinoma.5 A similar case was reported in 2006 in which the tumor also was found to be a low-grade adenocarcinoma arising from CHRPE.6 In the case reported herein, the eye was enucleated because of progressive tumor growth, extensive retinal detachment, intraocular inflammation, and profound, irreversible visual loss. Thus, 3 malignant neoplasms arising from CHRPE are known, and it is likely that more cases have occurred but have not been diagnosed clinically because they generally are, small and asymptomatic and are found in the peripheral fundus, where they can remain undetected.
The nomenclature for acquired tumors of the RPE is confusing because various authors have used terms like adenoma and adenocarcinoma to describe the benign and malignant forms. Histopathologically, these tumors are composed of a proliferation of either benign or malignant RPE cells without glandular features. Hence, the terms benign epithelioma and malignant epithelioma may be preferable to adenoma and adenocarcinoma, respectively.1 Characteristic clinical features of primary tumors of the RPE, including those that originate from CHRPE, include the development of retinal blood vessels that supply and drain the tumor and yellow lipoproteinaceous retinal and
2215
Ophthalmology Volume 116, Number 11, November 2009 subretinal exudation.1,7 These findings should differentiate RPE tumors from choroidal melanoma, which rarely have feeder vessels or significant exudation. Ancillary studies also can assist in clinical diagnosis. Fluorescein angiography generally accentuates the feeder vessels and shows mild hyperfluorescence of the mass. Ultrasonography shows an abruptly elevated so-call derby hat–shaped mass with medium to high internal reflectivity. With time, these RPE tumors cause exudative retinal detachment, intraocular inflammation, vitreous traction, posterior synechiae, and cataract.7 Although such diffuse intraocular inflammation becomes progressively worse as the tumor enlarges, it is uncertain whether the tumor induces the secondary inflammation or whether the chronic inflammation promotes the growth of the tumor. The pathogenesis of the tumor described here is uncertain. It is tempting to speculate that other reported neoplasms of the RPE may have originated from foci of CHRPE and that the underlying CHRPE eventually was obscured by the overlying mass. An interesting aspect of the tumor reported here was the intense infiltration of the mass by plasma cells. A retrospective review of a previously reported case also showed the presence of many plasma cells.5 What stimulates the plasma cell infiltration of these tumors is uncertain. The best management of tumors arising from CHRPE has not been established. In a prior series of acquired RPE tumors without evidence of CHRPE, 2 tumors progressed to blindness and phthisis despite local irradiation.7 One other case in which a pigment epithelial tumor was associated with massive destruction of the eye is known.8 Enucleation was performed rather than irradiation because there was no hope for useful vision and the progressive growth suggested that the tumor was malignant. In retrospect, earlier treatment would have been advisable. The authors currently are following up several cases of small nodular tumors arising from CHRPE and have been hesitant to treat them because they are relatively small and asymptomatic and the vertical growth has been slow. In view of the now-recognized natural course of some of these lesions, however, it may be prudent to treat them when lipoproteinaceous exudation first appears and when the elevated lesion is still relatively small, even though the vision may be normal. It is not yet determined whether such treatment should be by laser, cryother-
apy, photodynamic therapy, local resection, or local irradiation, but each case should be individualized according to the clinical situation. To the authors’ knowledge, no malignant epithelioma (adenocarcinoma) of the RPE has exhibited distant metastases. In summary, the current case suggests that malignant neoplasms may arise from CHRPE. However, tumors of the RPE seem to have no potential to metastasize.1,8 Nevertheless, they can cause exudative retinal detachment and blindness. Therefore, earlier treatment, rather than prolonged observation, may be justified for progressive lesions. The ideal treatment of this intriguing neoplasm remains to be determined.
References 1. Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In: Shields JA, Shields CL, eds. Intraocular Tumors. An Atlas and Textbook. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2008:432– 83. 2. Chamot L, Zografos L, Klainguti G. Fundus changes associated with congenital hypertrophy of the retinal pigment epithelium. Am J Ophthalmol 1993;115:154 – 61. 3. Shields CL, Mashayekhi A, Ho T, et al. Solitary congenital hypertrophy of the retinal pigment epithelium: clinical features and frequency of enlargement in 330 patients. Ophthalmology 2003;110:1968 –76. 4. Shields JA, Shields CL, Singh AD. Acquired tumors arising from congenital hypertrophy of the retinal pigment epithelium. Arch Ophthalmol 2000;118:637– 41. 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. Trichopoulos N, Augsburger JJ, Schneider S. Adenocarcinoma arising from congenital hypertrophy of the retinal pigment epithelium. Graefes Arch Clin Exp Ophthalmol 2006; 244:125– 8. 7. 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– 8. 8. Edelstein C, Shields CL, Shields JA, Eagle RC Jr. Presumed adenocarcinoma of the retinal pigment epithelium in a blind eye with a staphyloma. Arch Ophthalmol 1998;116:525– 8.
Footnotes and Financial Disclosures Originally received: December 8, 2008. Final revision: April 22, 2009. Accepted: April 24, 2009. Available online: September 10, 2009.
Manuscript no. 2008-1459.
1
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. 2
Department of Pathology, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
Supported by a donation from the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust (CLS), Philadelphia, Pennsylvania; the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); the LuEsther Mertz Retina Research Foundation (CLS); the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology (RCE), Philadelphia, Pennsylvania; and a donation from Michael, Bruce, and Ellen Ratner, New York, New York (CLS and JS).
3
Retina Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Correspondence: Jerry A. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: jerryshields@ comcast.net.