- Email: [email protected]
Progressive enlargement of acquired retinal astrocytoma in 2 cases
Progressive Enlargement of Acquired Retinal Astrocytoma in 2 Cases Carol L. Shields, MD,1 Jerry A. Shields, MD,1 Ralph C. Eagle, Jr, MD,2 Francis Cangemi, MD3 Purpose: To document 2 cases of progressively enlarging retinal astrocytoma that caused exudative retinal detachment, vitreous hemorrhage, and tumor seeding, simulating retinoblastoma in 1 case and choroidal melanoma in the other. Design: Interventional case reports. Participants: Two patients. Methods: Two patients with visual loss from an atypical, enlarging amelanotic retinal mass were evaluated. The first patient, a 14 year-old otherwise healthy girl, had a noncalcified gelatinous retinal mass with prepapillary involvement and surrounding retinal traction, as well as overlying vitreous hemorrhage and vitreous seeds. Over 37 months, the tumor grew in basal dimension from 4 mm to 10 mm. Retinal astrocytoma was suspected, but the presence of tumor enlargement and vitreous seeding raised concern for possible retinoblastoma. Fine-needle aspiration biopsy was performed. The second patient, a 33-year-old woman, had an amelanotic mass develop in the macula of her amblyopic left eye. Over 2 years, the mass enlarged to 9.5 mm in basal dimension and 6.3 mm in thickness, and total serous retinal detachment developed. Choroidal melanoma with retinal invasion was clinically suspected. Enucleation was performed. Results: In patient 1, cytologic examination revealed bland spindle cells with fibrillar cytoplasm consistent with an astrocytic tumor of the retina. Enucleation was subsequently performed because of continued tumor growth, progressive retinal detachment, and visual loss. Histopathologic examination confirmed astrocytoma of the retina and optic disc. In patient 2, enucleation revealed astrocytoma of the retina and optic disc with total retinal detachment. There was no evidence of systemic tuberous sclerosis in either patient. Conclusions: Retinal astrocytoma can show progressive enlargement, retinal detachment, and vitreous seeding, findings that can mislead the clinician toward the diagnosis of retinoblastoma or choroidal melanoma. Ophthalmology 2004;111:363–368 © 2004 by the American Academy of Ophthalmology.
Retinal astrocytic hamartoma is a benign congenital tumor that classically occurs in association with tuberous sclerosis or neurofibromatosis.1,2 This tumor can be solitary or multifocal and characteristically shows little change over decades, seldom requiring treatment.3 Associated tumor growth, vitreous hemorrhage, and vitreous seeds are rarely observed with this tumor.4,5 In contrast, acquired retinal or optic disc astrocytoma is a rare tumor, described in few reports in the literature during the past 70 years6 –18 (Table 1). It is a benign acquired solitary lesion, probably unrelated Originally received: January 22, 2003. Accepted: May 7, 2003. Manuscript no. 230022. 1 Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 2 Pathology Department, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 3 Vitreoretinal Associates of New Jersey, Ridgewood, New Jersey. Supported by the Rosenthal Award of the Macula Society (CLS), the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS), the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS), and the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital, Philadelphia, Pennsylvania (RCE). Reprint requests to Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107. E-mail: [email protected]. © 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
to tuberous sclerosis, with a propensity for progressive relentless enlargement, often necessitating enucleation.1,2 Astrocytic hamartoma and acquired astrocytoma are clinically similar lesions that occur within the sensory retina as a yellow-white mass. They might be difficult to differentiate clinically from retinoblastoma and other malignant tumors.1,2,16,19 In this report, we describe 2 cases of histopathologically confirmed solitary retinal astrocytoma unassociated with tuberous sclerosis that showed progressive growth and produced associated features such as vitreous seeds, vitreous hemorrhage, and exudative retinal detachment, simulating retinoblastoma in 1 case and choroidal melanoma in the other.
Case Reports Case 1 In February 1998, a 14-year-old Caucasian girl was seen with 2 months of blurred vision in her right eye. The visual acuity was 20/30 in the right eye and 20/20 in the left eye. The left eye was normal. The right eye demonstrated a white gelatinous retinal tumor with epipapillary involvement, measuring 4.0 mm ⫻ 3.0 mm in base and 2.5 mm in thickness (Fig 1). There were no dilated feeder vessels, exudation, or subretinal fluid. The lesion was surISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.05.009
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Ophthalmology Volume 111, Number 2, February 2004 Table 1. Review of Published Cases of Retinal/Optic Disc Astrocytoma not Associated with Tuberous Sclerosis or Neurofibromatosis
Date
Patient Age/ Race/ Gender
Marks et al6 Boles et al7 Foos et al8 Cleasby et al9 Jordano et al10 Reeser et al11
1939 1958 1965 1967 1974 1978
6 yr/W/M* 6 yr/W/F* 14 yr/W/F 20 mo/W/M 9 yr/F† 6 yr/W/M
Retina Retina Retina Retina Retina Retina
Ramsay et al12 Jakobiec et al13 Ulbright et al14 Arnold et al15 Bornfeld et al16 Sharma et al17 Lee et al18 Shields C et al (present cases)
1979 1983 1984 1985 1987 1991 1996 2002
41 yr/W/M 5 mo/M† 13 mo/F† 16/W/F 56 yr/W/M 2 yr/F† 3 yr/F† 35/W/F 14/W/F
Authors
Tumor Course (mos)
Tumor Location juxtapapillary juxtapapillary juxtapapillary juxtapapillary juxtapapillary juxtapapillary
Preoperative Diagnosis
Growth (62) Growth (12) Growth (204) NA Growth (8) Growth (84)
NA NA Retinal angioma Retinoblastoma Tuberculoma Astrocytoma
Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Optic disc Retina periphery Retina juxtapapillary
NA NA NA Growth (7) Growth (4) NA NA Growth (24)
Retina juxtapapillary
Growth (37)
Treatment
Pathology Diagnosis Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma
Retinal angioma Retinoblastoma Retinoblastoma NA Choroidal melanoma Retinoblastoma Retinoblastoma Choroidal melanoma
Enucleation Enucleation Enucleation Enucleation Enucleation External radiation ⫹ enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation
Astrocytoma
Enucleation
Astrocytoma
Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma
F ⫽ female; M ⫽ male; NA ⫽ not applicable, because the patient was treated promptly, or tumor course was not mentioned in the report; W ⫽ white. The data in this table were collected in May 2002 from a review of published papers from a MEDLINE search using the key words retina astrocytoma, retina astrocytic hamartoma, optic disc astrocytoma, optic disc astrocytic hamartoma. Further data were acquired by reviewing references from the acquired articles. *No mention of an evaluation for tuberous sclerosis or neurofibromatosis in this patient. † Race not indicated.
rounded by dramatic preretinal fibroglial tissue extending irregularly for 4 mm on all margins, and adjacent fine overlying vitreous seeds were noted. The vitreous seeds were congealed, gelatinous opacities, larger than vitreous inflammatory cells and more condensed than retinoblastoma seeds. Furthermore, in the periphery were subtle, multifocal areas of retinal pigment epithelial atrophy. Ocular ultrasonography depicted the mass as plateau-shaped and noncalcified. Intravenous fluorescein angiography showed multifocal pinpoint areas of hyperfluorescence within the mass in the arterial phase and diffuse homogeneous hyperfluorescence of the mass in the late phase. Retinal astrocytic hamartoma versus astrocytoma was suspected, and observation was advised. There was no personal or family history of tuberous sclerosis or neurofibromatosis. Magnetic resonance imaging of the brain was unremarkable. On follow-up in March 1999, the mass had enlarged to 6.0 mm in basal diameter and 2.5 mm in thickness. In September 1999, symptomatic dense vitreous hemorrhage was found and cautiously removed by vitrectomy, yielding only red blood cells on cytology. In December 1999, the visual acuity had decreased to 20/200 from tumor encroachment into the foveola, because the lesion had enlarged to 7.0 mm in basal diameter and 3.9 mm in thickness. Fine-needle aspiration biopsy was performed by the trans pars plana, transvitreal route,19 and cytopathologic assessment disclosed slender spindle cells with bland nuclei and no mitoses, consistent with astrocytic tumor (Fig 1). In July 2000, progressive enlargement of the mass to 8.5 mm in basal diameter and 4.0 mm in thickness, and the development of extensive intraretinal perivascular exudation, subretinal exudation, and subretinal fluid were noted. In March 2001, the visual acuity had decreased to 20/400 from tumor involvement of the macula, and the tumor’s basal diameter was 10.0 mm and its thickness was 5.5 mm (Fig 1). Because of the tumor’s progressive enlargement and involvement of the optic disc and macula, progressive retinal detachment, and visual loss, radiotherapy or enucleation were advised, and enucleation was subsequently performed.
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Gross examination revealed a bilobed epipapillary and retinal mass with associated subretinal fluid and yellow exudation. Histopathologic studies disclosed the retinal mass overhanging the optic disc. One half of the tumor arose from the outer retina and filled the subretinal space, whereas the other half was more endophytic. The tumor was composed of fascicles of bland spindle cells with fine fibrillar cytoplasm consistent with glial cells (Fig 1). Nuclei were bland, and mitotic activity was not evident. Immunohistochemistry revealed the cells to be reactive to glial fibrillary acidic protein and nonreactive to melanoma-specific antigen (HMB 45). Subretinal fluid with lipid and partial photoreceptor and optic nerve atrophy were present. The final diagnosis was retinal astrocytoma, with invasion of the vitreous cavity and subretinal space.
Case 2 A 33-year-old woman with congenital esotropia and amblyopia of the left eye was noted by her optometrist in 1982 to have a mass in the posterior segment of the left eye. One year later, photopsia and visual loss developed. On referral to us, her visual acuity was 20/20 in the right eye and bare light perception in the left eye. There was a nodular amelanotic mass with full-thickness retinal invasion in the macular region overhanging the optic disc (Fig 2). The mass measured 9.5 mm in basal diameter and 6.3 mm in thickness and was surrounded by total serous retinal detachment with equatorial perivascular exudation. Ocular ultrasonography disclosed a nodular echogenic mass on B scan and medium internal reflectivity on A scan. Fluorescein angiography showed prominent vascularity in the arterial phase with diffuse late hyperfluorescence. Amelanotic choroidal melanoma was a diagnostic consideration, and enucleation was performed. Gross pathologic findings revealed the amelanotic mass to be entirely within the retina. The tumor overhung the optic disc region, and there was no choroidal component. Microscopically,
Shields et al 䡠 Retinal Astrocytoma the tumor was composed of a matrix of well-differentiated glial cells with round or slightly elongated basophilic vacuolated nuclei (Fig 2). Rare mitotic figures were noted. The Bodian stain was negative, and Luxol fast blue stain showed scattered positivity. The final diagnosis was retinal astrocytoma of the sensory retina and optic disc.
Discussion Retinal astrocytic tumors are uncommon and are generally subdivided into 1 of 3 types, including astrocytic hamartoma, acquired astrocytoma, and retinal gliosis.1,2,20 Retinal gliosis is typically a reactive process, usually occurring after posterior segment inflammation or infection.20 If focal or nodular, the process appears as a dense white mass within or superficial to the retina. Signs of previous retinal inflammation and retinal pigment epithelial proliferation are usually present. If diffuse, the gliosis appears more extensive and can obliterate a view of the underlying degenerated retina. Retinal astrocytic hamartoma is classically a benign, stable tumor, most often found in association with tuberous sclerosis (Bourneville’s disease) or neurofibromatosis (von Recklinghausen’s disease).2,3 This gelatinous, yellow-white tumor can appear solitary or multifocal within 1 or both eyes. A review of 37 retinal astrocytic hamartomas in 16 patients with tuberous sclerosis revealed no growth of any tumor over an average of 16 years’ follow-up.3 It has been stated that if growth occurs, it is usually so slow that it is detected only over decades.21 Despite the lack of growth, the clinical appearance of retinal astrocytic hamartoma can change over time, with progressive calcification of the mass.22 Acquired retinal astrocytoma is a gelatinous, yellowwhite tumor that occurs sporadically in patients without systemic tuberous sclerosis or neurofibromatosis. Its appearance might superficially resemble an astrocytic hamartoma, but it lacks calcium, and its behavior is more aggressive, with progressive tumor growth, often simulating retinoblastoma or amelanotic choroidal melanoma. This rare tumor has been recognized in only a few published cases6 –18 (Table 1). Bornfeld et al16 reported such a progressive tumor with progression in a 56-year-old man with no evident tuberous sclerosis but with an epipapillary astrocytoma, simulating a juxtapapillary choroidal melanoma. In their case, the tumor grew over 4 months, and subsequent enucleation revealed the pathologic diagnosis of astrocytoma of the retina.16 They and others have observed that such acquired astrocytic tumors, unassociated with tuberous sclerosis, manifest as a single tumor, generally located at the optic disc, and sometimes with retinal exudation6 – 8,10,12,16 (Table 1). These features were evident in both of our cases. Despite the benign cellularity of acquired retinal astrocytoma, this tumor shows a remarkable tendency for progression, even leading to total retinal detachment and secondary glaucoma.10,16,18 In 1978, Reeser et al11 reported a 6-yearold boy with a retinal astrocytoma, not associated with tuberous sclerosis, which showed progressive enlargement over 7 years, leading to enucleation. Ramsay et al,12 in 1979, reported a 41-year-old man with a juxtapapillary retinal astrocytoma that showed marked uptake of radioac-
tive phosphorus (32P test) and progressive enlargement. In their case, histopathologic studies of the enucleated eye confirmed the diagnosis of benign retinal astrocytoma in a patient with no evidence of tuberous sclerosis. It should be realized, however, that dramatic growth rarely occurs with astrocytic tumors associated with tuberous sclerosis. 5,23 We have observed this in 4 patients, 1 of whom was recently published, in whom dramatic growth of a retinal astrocytic tumor filled the entire vitreous cavity in a 12-year-old girl with tuberous sclerosis.5 Later enucleation of that eye revealed invasive giant cell astrocytoma. In case 1 in this report, tumor enlargement from 4.0 to 10.0 mm in basal diameter and from 2.5 mm to 5.5 mm in thickness over 37 months was noted. These findings prompted suspicion for atypical, slow-growing retinoblastoma, but the clinical features were more typical of acquired retinal astrocytoma. Fine-needle aspiration biopsy confirmed the astrocytic nature of the tumor. Even though fine-needle aspiration biopsy was helpful, it should be understood that fine-needle aspiration biopsy could theoretically be dangerous in cases of retinoblastoma.2,19,21 Previous reports regarding needle biopsy for retinal tumors in children have issued a warning regarding the potential danger of extraocular tumor spread if the tumor proves to be retinoblastoma. Thus, if the clinician suspects retinoblastoma in an eye of a child, proper treatment for retinoblastoma without needle biopsy is suggested. If concern regarding a diagnosis continues, a second opinion by a retinoblastoma specialist is advised. Several clinical features suggested the diagnosis of acquired retinal astrocytoma rather than retinoblastoma in case 1. First, the tumor appeared gelatinous, with surrounding retinal traction. Retinal traction is commonly found with astrocytic tumors and not with retinoblastoma.1 Second, quadrantic peripheral retinal pigment epithelial atrophy was seen. These retinal pigment epithelial alterations are often found in association with astrocytic tumors but almost never with retinoblastoma.1 Third, extensive yellow retinal exudation developed in this case, a finding that is notably rare with retinoblastoma. Other findings, such as the lack of calcification, are typical for acquired astrocytoma but can occasionally occur with astrocytic hamartoma and retinoblastoma. In addition, both astrocytic hamartoma and retinoblastoma are usually diagnosed in young children,24 whereas acquired retinal astrocytoma generally occurs in somewhat older children and adults. Fine, gelatinous vitreous seeds were noted immediately overlying the mass in case 1. The association of vitreous seeds with a white retinal mass in a child should strongly suggest retinoblastoma. Active vitreous seeds from retinoblastoma are translucent and gelatinous when small but assume a whiter, softer presentation with a “cotton candy” appearance when larger than approximately 0.25 mm. It also should be realized that vitreous seeds rarely occur with astrocytic hamartoma. DeJuan et al4 reported a 26-year-old man with tuberous sclerosis who had diffuse bilateral vitreous opacities overlying calcified retinal tumors. The vitreous cells raised suspicion for bilateral toxoplasmosis and prompted oral medications, but later vitrectomy revealed spindle-shaped cells with fine cytoplasmic processes sug-
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Shields et al 䡠 Retinal Astrocytoma Figure 1. A 14-year-old girl with epipapillary retinal astrocytic tumor. A, February 1998. The tumor is gelatinous and overhangs the optic disc. B, February 1998. Fluorescein angiogram, arterial phase. The mass involves the optic disc and shows multifocal pinpoint areas of hyperfluorescence. C, February 1998. Fluorescein angiogram, late phase. The mass is hyperfluorescent, and there is mild surrounding hyperfluorescence in the subretinal fluid. D, February 1998. Ocular ultrasonography, B scan. The dome-shaped mass is echogenic and measures 2.5 mm in thickness. The optic nerve is visualized in the orbit. There was no evidence of intralesional calcium. E, April 2000. Cytopathology of fine-needle aspiration biopsy reveals slender spindle cells with bland nuclei and no mitosis, consistent with astrocytic tumor (stain, Papanicolaou; original magnification, ⫻600). F, March 2001. The tumor has grown both in basal diameter and thickness. G, March 2001. Ocular ultrasonography, B scan. The dome-shaped mass measures 5.5 mm in thickness. Subretinal fluid is noted inferiorly. H, March 2001. Gross examination of the globe reveals the white retinal mass with surrounding exudative retinal detachment. I, March 2001. Low-power microscopy of the enucleated globe demonstrates a mass arising from the retina. Note the subretinal fluid (stain, hematoxylin– eosin; original magnification, ⫻5). J, March 2001. High-power microscopy reveals fascicles of bland spindle cells with finely fibrillar cytoplasm consistent with the diagnosis of astrocytoma (stain, hematoxylin– eosin; original magnification, ⫻250). 4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
gestive of astrocytic tumor seeds. DeJuan et al commented that vitreous seeding by astrocytic hamartoma was extremely rare but had been recognized decades previously by Van der Hoeve,25 who suggested that cystic degeneration of astrocytic hamartoma allowed small pieces of tumor to detach and float in the vitreous. Vitreous hemorrhage has also previously been recognized with astrocytic hamartoma in patients with tuberous sclerosis, as well as in those with retinoblastoma and choroidal melanoma.26 –28 We presume that both of our patients had an acquired retinal astrocytoma rather than astrocytic hamartoma. However, it is possible that each had a forme fruste of tuberous sclerosis, manifesting as a solitary retinal lesion. There have been a few cases of retinal astrocytoma reported in infants and young children without evidence of tuberous sclerosis,6,7,9 –11,13,14,17,18 but we caution that longer follow-up for other manifestations of tuberous sclerosis in the first 1 or 2 decades of life would be important in such cases (Table 1). Our cases, however, are similar to other reported cases of adults 8,12,16 with solitary retinal astrocytoma unassociated with tuberous sclerosis. Unlike the astrocytic hamartoma of tuberous sclerosis, the presumed acquired astrocytoma is more aggressive and lacks clinical evidence of calcium. Therefore, it seems to be a different type of glial tumor. The progressive growth of retinal astrocytoma is similar to that of low-grade astrocytoma of the brain. In the brain, these tumors are seen in young patients at a mean age of 27 years as a diffuse or circumscribed mass, showing little response to radiation.29 The affected patients often have a long history of symptoms. Despite the benign cytology, low-grade brain astrocytomas are progressive, and recurrence after resection is common, leading to only 25% survival at 10 years.30 In summary, we present 2 patients, a teenager and an adult, each with a rare retinal tumor, histopathologically proven to be a retinal astrocytoma. We suggest that they represent acquired lesions, unassociated with tuberous sclerosis and similar to the brain astrocytoma. They both
showed progressive enlargement and associated findings such as vitreous hemorrhage, vitreous seeding, and exudative retinal detachment. This tumor should be differentiated from intraocular malignancy, particularly retinoblastoma and choroidal melanoma.
References 1. Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia: Lippincott Williams and Wilkins; 1999:269 – 86. 2. Shields JA, Shields CL. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders; 1992:421–36. 3. Zimmer-Galler IE, Robertson DM. Long-term observation of retinal lesions in tuberous sclerosis. Am J Ophthalmol 1995; 119:318 –24. 4. de Juan E Jr, Green WR, Gupta PK, Baranano EC. Vitreous seeding by retinal astrocytic hamartoma in a patient with tuberous sclerosis. Retina 1984;4:100 –2. 5. Gunduz K, Eagle RC Jr, Shields CL, et al. Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis. Ophthalmology 1999;106:639 – 42. 6. Marks EO, Willis RA, Anderson JR. Glioma of the optic disc. Trans Ophthalmol Soc Aust 1939;1:46 –54. 7. Boles WM, Naugle TC, Samson CLM. Glioma of the optic nerve. Arch Ophthalmol 1958;59:229 –31. 8. Foos RY, Straatsma BR, Allen RA. Astrocytoma of the optic nerve head. Arch Ophthalmol 1965;74:319 –26. 9. Cleasby GW, Fung WE, Shekter WB. Astrocytoma of the retina. Report of two cases. Am J Ophthalmol 1967;64(suppl 3):633–7. 10. Jordano J, Galera H, Toro M, Carreras B. Astrocytoma of the retina. Report of a case. Br J Ophthalmol 1974;58:555–9. 11. Reeser FH, Aaberg TM, Van Horn DL. Astrocytic hamartoma of the retina not associated with tuberous sclerosis. Am J Ophthalmol 1978;86:688 –98. 12. Ramsay RC, Kinyoun JL, Hill CW, et al. Retinal astrocytoma. Am J Ophthalmol 1979;88:32– 6. 13. Jakobiec FA, Brodie SE, Haik B, Iwamoto T. Giant cell astrocytoma of the retina. A tumor of possible Mueller cell origin. Ophthalmology 1983;90:1565–76.
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
Figure 2. A 35-year-old woman with an amelanotic macular tumor and total retinal detachment. A, July 1984. The amelanotic tumor is seen deep to the retinal vessels and overhangs the optic disc. B, July 1984. Fluorescein angiogram, arterial phase. Prominent intrinsic vessels are seen within the mass. C, July 1984. Fluorescein angiogram, late phase. Diffuse hyperfluorescence of the tumor is noted. D, July 1984. Ocular ultrasonography, B scan. The nodular echogenic mass and retinal detachment are visualized. E, July 1984. Low-power microscopy of the enucleated globe demonstrates the mass arising from the juxtapapillary retina and prepapillary region. Note the subretinal fluid (stain, hematoxylin– eosin; original magnification, ⫻4). F, July 1984. High-power microscopy reveals fascicles of bland spindle cells with round or slightly elongated basophilic vacuolated nuclei consistent with the diagnosis of astrocytoma (stain, hematoxylin– eosin; original magnification, ⫻100).
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Ophthalmology Volume 111, Number 2, February 2004 14. Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina. Differentiation of sporadic tumors from phakomatosisassociated tumors. Arch Pathol Lab Med 1984;108:160 –3. 15. Arnold AC, Hepler RS, Yee RW, et al. Solitary retinal astrocytoma. Surv Ophthalmol 1985;30(3):173– 81. 16. Bornfeld N, Messmer EP, Theodossiadis G, et al. Giant cell astrocytoma of the retina. Clinicopathologic report of a case not associated with Bourneville’s disease. Retina 1987;7: 183–9. 17. Sharma A, Ram J, Gupta A. Solitary retinal astrocytoma. Acta Ophthalmol (Copenh) 1991;69:113– 6. 18. Lee JA, Harvey P, Finlay RD, Berry PJ. Solitary astrocytoma of the retina in a child. Br J Ophthalmol 1996;80:674 –5. 19. Shields JA, Shields CL, Ehya H, et al. Atypical retina astrocytic hamartoma diagnosed by fine-needle biopsy. Ophthalmology 1996;103:949 –52. 20. Yanoff M, Zimmerman LE, Davis RL. Massive gliosis of the retina. Int Ophthalmol Clin 1971;11:211–29. 21. Robertson DM. Fine-needle biopsy and retinoblastoma [letter]. Ophthalmology 1997;104:567– 8. 22. Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis. Arch Ophthalmol 1976;94:1277– 80.
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23. Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in tuberous sclerosis. Retina 1993;13:155–9. 24. Shields CL, Shields JA, Shah P. Retinoblastoma in older children. Ophthalmology 1991;98:395–9. 25. Van der Hoeve J. Augengeschwulste bei der tuberosen Hirnsklerose (Bourneville) und verwandten krankheitne V [English translation]. Graefes Arch Ophthalmol 1921;105:880 – 98. 26. Atkinson A, Sanders MD, Wong V. Vitreous haemorrhage in tuberous sclerosis. Report of two cases. Br J Ophthalmol 1973;57:773–9. 27. Kroll AJ, Ricker DP, Robb RM, Albert DM. Vitreous hemorrhage complicating retinal astrocytic hamartoma. Surv Ophthalmol 1981;26:31– 8. 28. Byrnes G, Shields CL, Shields JA, et al. Retinoblastoma presenting with spontaneous hyphema and dislocated lens. J Pediatr Ophthalmol Strabismus 1993;30:334 – 6. 29. Scanlon PW, Taylor WF. Radiotherapy of intracranial astrocytomas: analysis of 417 cases treated from 1960 to 1969; Neurosurgery 1979;5:301– 8. 30. Fazekas JT. Treatment of grades I and II brain astrocytomas. The role of radiotherapy. Int J Radiat Oncol Biol Phys 1977; 2:661– 6.
Retinal astrocytic hamartoma is a benign congenital tumor that classically occurs in association with tuberous sclerosis or neurofibromatosis.1,2 This tumor can be solitary or multifocal and characteristically shows little change over decades, seldom requiring treatment.3 Associated tumor growth, vitreous hemorrhage, and vitreous seeds are rarely observed with this tumor.4,5 In contrast, acquired retinal or optic disc astrocytoma is a rare tumor, described in few reports in the literature during the past 70 years6 –18 (Table 1). It is a benign acquired solitary lesion, probably unrelated Originally received: January 22, 2003. Accepted: May 7, 2003. Manuscript no. 230022. 1 Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 2 Pathology Department, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. 3 Vitreoretinal Associates of New Jersey, Ridgewood, New Jersey. Supported by the Rosenthal Award of the Macula Society (CLS), the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS), the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS), and the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital, Philadelphia, Pennsylvania (RCE). Reprint requests to Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107. E-mail: [email protected]. © 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
to tuberous sclerosis, with a propensity for progressive relentless enlargement, often necessitating enucleation.1,2 Astrocytic hamartoma and acquired astrocytoma are clinically similar lesions that occur within the sensory retina as a yellow-white mass. They might be difficult to differentiate clinically from retinoblastoma and other malignant tumors.1,2,16,19 In this report, we describe 2 cases of histopathologically confirmed solitary retinal astrocytoma unassociated with tuberous sclerosis that showed progressive growth and produced associated features such as vitreous seeds, vitreous hemorrhage, and exudative retinal detachment, simulating retinoblastoma in 1 case and choroidal melanoma in the other.
Case Reports Case 1 In February 1998, a 14-year-old Caucasian girl was seen with 2 months of blurred vision in her right eye. The visual acuity was 20/30 in the right eye and 20/20 in the left eye. The left eye was normal. The right eye demonstrated a white gelatinous retinal tumor with epipapillary involvement, measuring 4.0 mm ⫻ 3.0 mm in base and 2.5 mm in thickness (Fig 1). There were no dilated feeder vessels, exudation, or subretinal fluid. The lesion was surISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.05.009
363
Ophthalmology Volume 111, Number 2, February 2004 Table 1. Review of Published Cases of Retinal/Optic Disc Astrocytoma not Associated with Tuberous Sclerosis or Neurofibromatosis
Date
Patient Age/ Race/ Gender
Marks et al6 Boles et al7 Foos et al8 Cleasby et al9 Jordano et al10 Reeser et al11
1939 1958 1965 1967 1974 1978
6 yr/W/M* 6 yr/W/F* 14 yr/W/F 20 mo/W/M 9 yr/F† 6 yr/W/M
Retina Retina Retina Retina Retina Retina
Ramsay et al12 Jakobiec et al13 Ulbright et al14 Arnold et al15 Bornfeld et al16 Sharma et al17 Lee et al18 Shields C et al (present cases)
1979 1983 1984 1985 1987 1991 1996 2002
41 yr/W/M 5 mo/M† 13 mo/F† 16/W/F 56 yr/W/M 2 yr/F† 3 yr/F† 35/W/F 14/W/F
Authors
Tumor Course (mos)
Tumor Location juxtapapillary juxtapapillary juxtapapillary juxtapapillary juxtapapillary juxtapapillary
Preoperative Diagnosis
Growth (62) Growth (12) Growth (204) NA Growth (8) Growth (84)
NA NA Retinal angioma Retinoblastoma Tuberculoma Astrocytoma
Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Retina juxtapapillary Optic disc Retina periphery Retina juxtapapillary
NA NA NA Growth (7) Growth (4) NA NA Growth (24)
Retina juxtapapillary
Growth (37)
Treatment
Pathology Diagnosis Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma
Retinal angioma Retinoblastoma Retinoblastoma NA Choroidal melanoma Retinoblastoma Retinoblastoma Choroidal melanoma
Enucleation Enucleation Enucleation Enucleation Enucleation External radiation ⫹ enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation
Astrocytoma
Enucleation
Astrocytoma
Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma Astrocytoma
F ⫽ female; M ⫽ male; NA ⫽ not applicable, because the patient was treated promptly, or tumor course was not mentioned in the report; W ⫽ white. The data in this table were collected in May 2002 from a review of published papers from a MEDLINE search using the key words retina astrocytoma, retina astrocytic hamartoma, optic disc astrocytoma, optic disc astrocytic hamartoma. Further data were acquired by reviewing references from the acquired articles. *No mention of an evaluation for tuberous sclerosis or neurofibromatosis in this patient. † Race not indicated.
rounded by dramatic preretinal fibroglial tissue extending irregularly for 4 mm on all margins, and adjacent fine overlying vitreous seeds were noted. The vitreous seeds were congealed, gelatinous opacities, larger than vitreous inflammatory cells and more condensed than retinoblastoma seeds. Furthermore, in the periphery were subtle, multifocal areas of retinal pigment epithelial atrophy. Ocular ultrasonography depicted the mass as plateau-shaped and noncalcified. Intravenous fluorescein angiography showed multifocal pinpoint areas of hyperfluorescence within the mass in the arterial phase and diffuse homogeneous hyperfluorescence of the mass in the late phase. Retinal astrocytic hamartoma versus astrocytoma was suspected, and observation was advised. There was no personal or family history of tuberous sclerosis or neurofibromatosis. Magnetic resonance imaging of the brain was unremarkable. On follow-up in March 1999, the mass had enlarged to 6.0 mm in basal diameter and 2.5 mm in thickness. In September 1999, symptomatic dense vitreous hemorrhage was found and cautiously removed by vitrectomy, yielding only red blood cells on cytology. In December 1999, the visual acuity had decreased to 20/200 from tumor encroachment into the foveola, because the lesion had enlarged to 7.0 mm in basal diameter and 3.9 mm in thickness. Fine-needle aspiration biopsy was performed by the trans pars plana, transvitreal route,19 and cytopathologic assessment disclosed slender spindle cells with bland nuclei and no mitoses, consistent with astrocytic tumor (Fig 1). In July 2000, progressive enlargement of the mass to 8.5 mm in basal diameter and 4.0 mm in thickness, and the development of extensive intraretinal perivascular exudation, subretinal exudation, and subretinal fluid were noted. In March 2001, the visual acuity had decreased to 20/400 from tumor involvement of the macula, and the tumor’s basal diameter was 10.0 mm and its thickness was 5.5 mm (Fig 1). Because of the tumor’s progressive enlargement and involvement of the optic disc and macula, progressive retinal detachment, and visual loss, radiotherapy or enucleation were advised, and enucleation was subsequently performed.
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Gross examination revealed a bilobed epipapillary and retinal mass with associated subretinal fluid and yellow exudation. Histopathologic studies disclosed the retinal mass overhanging the optic disc. One half of the tumor arose from the outer retina and filled the subretinal space, whereas the other half was more endophytic. The tumor was composed of fascicles of bland spindle cells with fine fibrillar cytoplasm consistent with glial cells (Fig 1). Nuclei were bland, and mitotic activity was not evident. Immunohistochemistry revealed the cells to be reactive to glial fibrillary acidic protein and nonreactive to melanoma-specific antigen (HMB 45). Subretinal fluid with lipid and partial photoreceptor and optic nerve atrophy were present. The final diagnosis was retinal astrocytoma, with invasion of the vitreous cavity and subretinal space.
Case 2 A 33-year-old woman with congenital esotropia and amblyopia of the left eye was noted by her optometrist in 1982 to have a mass in the posterior segment of the left eye. One year later, photopsia and visual loss developed. On referral to us, her visual acuity was 20/20 in the right eye and bare light perception in the left eye. There was a nodular amelanotic mass with full-thickness retinal invasion in the macular region overhanging the optic disc (Fig 2). The mass measured 9.5 mm in basal diameter and 6.3 mm in thickness and was surrounded by total serous retinal detachment with equatorial perivascular exudation. Ocular ultrasonography disclosed a nodular echogenic mass on B scan and medium internal reflectivity on A scan. Fluorescein angiography showed prominent vascularity in the arterial phase with diffuse late hyperfluorescence. Amelanotic choroidal melanoma was a diagnostic consideration, and enucleation was performed. Gross pathologic findings revealed the amelanotic mass to be entirely within the retina. The tumor overhung the optic disc region, and there was no choroidal component. Microscopically,
Shields et al 䡠 Retinal Astrocytoma the tumor was composed of a matrix of well-differentiated glial cells with round or slightly elongated basophilic vacuolated nuclei (Fig 2). Rare mitotic figures were noted. The Bodian stain was negative, and Luxol fast blue stain showed scattered positivity. The final diagnosis was retinal astrocytoma of the sensory retina and optic disc.
Discussion Retinal astrocytic tumors are uncommon and are generally subdivided into 1 of 3 types, including astrocytic hamartoma, acquired astrocytoma, and retinal gliosis.1,2,20 Retinal gliosis is typically a reactive process, usually occurring after posterior segment inflammation or infection.20 If focal or nodular, the process appears as a dense white mass within or superficial to the retina. Signs of previous retinal inflammation and retinal pigment epithelial proliferation are usually present. If diffuse, the gliosis appears more extensive and can obliterate a view of the underlying degenerated retina. Retinal astrocytic hamartoma is classically a benign, stable tumor, most often found in association with tuberous sclerosis (Bourneville’s disease) or neurofibromatosis (von Recklinghausen’s disease).2,3 This gelatinous, yellow-white tumor can appear solitary or multifocal within 1 or both eyes. A review of 37 retinal astrocytic hamartomas in 16 patients with tuberous sclerosis revealed no growth of any tumor over an average of 16 years’ follow-up.3 It has been stated that if growth occurs, it is usually so slow that it is detected only over decades.21 Despite the lack of growth, the clinical appearance of retinal astrocytic hamartoma can change over time, with progressive calcification of the mass.22 Acquired retinal astrocytoma is a gelatinous, yellowwhite tumor that occurs sporadically in patients without systemic tuberous sclerosis or neurofibromatosis. Its appearance might superficially resemble an astrocytic hamartoma, but it lacks calcium, and its behavior is more aggressive, with progressive tumor growth, often simulating retinoblastoma or amelanotic choroidal melanoma. This rare tumor has been recognized in only a few published cases6 –18 (Table 1). Bornfeld et al16 reported such a progressive tumor with progression in a 56-year-old man with no evident tuberous sclerosis but with an epipapillary astrocytoma, simulating a juxtapapillary choroidal melanoma. In their case, the tumor grew over 4 months, and subsequent enucleation revealed the pathologic diagnosis of astrocytoma of the retina.16 They and others have observed that such acquired astrocytic tumors, unassociated with tuberous sclerosis, manifest as a single tumor, generally located at the optic disc, and sometimes with retinal exudation6 – 8,10,12,16 (Table 1). These features were evident in both of our cases. Despite the benign cellularity of acquired retinal astrocytoma, this tumor shows a remarkable tendency for progression, even leading to total retinal detachment and secondary glaucoma.10,16,18 In 1978, Reeser et al11 reported a 6-yearold boy with a retinal astrocytoma, not associated with tuberous sclerosis, which showed progressive enlargement over 7 years, leading to enucleation. Ramsay et al,12 in 1979, reported a 41-year-old man with a juxtapapillary retinal astrocytoma that showed marked uptake of radioac-
tive phosphorus (32P test) and progressive enlargement. In their case, histopathologic studies of the enucleated eye confirmed the diagnosis of benign retinal astrocytoma in a patient with no evidence of tuberous sclerosis. It should be realized, however, that dramatic growth rarely occurs with astrocytic tumors associated with tuberous sclerosis. 5,23 We have observed this in 4 patients, 1 of whom was recently published, in whom dramatic growth of a retinal astrocytic tumor filled the entire vitreous cavity in a 12-year-old girl with tuberous sclerosis.5 Later enucleation of that eye revealed invasive giant cell astrocytoma. In case 1 in this report, tumor enlargement from 4.0 to 10.0 mm in basal diameter and from 2.5 mm to 5.5 mm in thickness over 37 months was noted. These findings prompted suspicion for atypical, slow-growing retinoblastoma, but the clinical features were more typical of acquired retinal astrocytoma. Fine-needle aspiration biopsy confirmed the astrocytic nature of the tumor. Even though fine-needle aspiration biopsy was helpful, it should be understood that fine-needle aspiration biopsy could theoretically be dangerous in cases of retinoblastoma.2,19,21 Previous reports regarding needle biopsy for retinal tumors in children have issued a warning regarding the potential danger of extraocular tumor spread if the tumor proves to be retinoblastoma. Thus, if the clinician suspects retinoblastoma in an eye of a child, proper treatment for retinoblastoma without needle biopsy is suggested. If concern regarding a diagnosis continues, a second opinion by a retinoblastoma specialist is advised. Several clinical features suggested the diagnosis of acquired retinal astrocytoma rather than retinoblastoma in case 1. First, the tumor appeared gelatinous, with surrounding retinal traction. Retinal traction is commonly found with astrocytic tumors and not with retinoblastoma.1 Second, quadrantic peripheral retinal pigment epithelial atrophy was seen. These retinal pigment epithelial alterations are often found in association with astrocytic tumors but almost never with retinoblastoma.1 Third, extensive yellow retinal exudation developed in this case, a finding that is notably rare with retinoblastoma. Other findings, such as the lack of calcification, are typical for acquired astrocytoma but can occasionally occur with astrocytic hamartoma and retinoblastoma. In addition, both astrocytic hamartoma and retinoblastoma are usually diagnosed in young children,24 whereas acquired retinal astrocytoma generally occurs in somewhat older children and adults. Fine, gelatinous vitreous seeds were noted immediately overlying the mass in case 1. The association of vitreous seeds with a white retinal mass in a child should strongly suggest retinoblastoma. Active vitreous seeds from retinoblastoma are translucent and gelatinous when small but assume a whiter, softer presentation with a “cotton candy” appearance when larger than approximately 0.25 mm. It also should be realized that vitreous seeds rarely occur with astrocytic hamartoma. DeJuan et al4 reported a 26-year-old man with tuberous sclerosis who had diffuse bilateral vitreous opacities overlying calcified retinal tumors. The vitreous cells raised suspicion for bilateral toxoplasmosis and prompted oral medications, but later vitrectomy revealed spindle-shaped cells with fine cytoplasmic processes sug-
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Shields et al 䡠 Retinal Astrocytoma Figure 1. A 14-year-old girl with epipapillary retinal astrocytic tumor. A, February 1998. The tumor is gelatinous and overhangs the optic disc. B, February 1998. Fluorescein angiogram, arterial phase. The mass involves the optic disc and shows multifocal pinpoint areas of hyperfluorescence. C, February 1998. Fluorescein angiogram, late phase. The mass is hyperfluorescent, and there is mild surrounding hyperfluorescence in the subretinal fluid. D, February 1998. Ocular ultrasonography, B scan. The dome-shaped mass is echogenic and measures 2.5 mm in thickness. The optic nerve is visualized in the orbit. There was no evidence of intralesional calcium. E, April 2000. Cytopathology of fine-needle aspiration biopsy reveals slender spindle cells with bland nuclei and no mitosis, consistent with astrocytic tumor (stain, Papanicolaou; original magnification, ⫻600). F, March 2001. The tumor has grown both in basal diameter and thickness. G, March 2001. Ocular ultrasonography, B scan. The dome-shaped mass measures 5.5 mm in thickness. Subretinal fluid is noted inferiorly. H, March 2001. Gross examination of the globe reveals the white retinal mass with surrounding exudative retinal detachment. I, March 2001. Low-power microscopy of the enucleated globe demonstrates a mass arising from the retina. Note the subretinal fluid (stain, hematoxylin– eosin; original magnification, ⫻5). J, March 2001. High-power microscopy reveals fascicles of bland spindle cells with finely fibrillar cytoplasm consistent with the diagnosis of astrocytoma (stain, hematoxylin– eosin; original magnification, ⫻250). 4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
gestive of astrocytic tumor seeds. DeJuan et al commented that vitreous seeding by astrocytic hamartoma was extremely rare but had been recognized decades previously by Van der Hoeve,25 who suggested that cystic degeneration of astrocytic hamartoma allowed small pieces of tumor to detach and float in the vitreous. Vitreous hemorrhage has also previously been recognized with astrocytic hamartoma in patients with tuberous sclerosis, as well as in those with retinoblastoma and choroidal melanoma.26 –28 We presume that both of our patients had an acquired retinal astrocytoma rather than astrocytic hamartoma. However, it is possible that each had a forme fruste of tuberous sclerosis, manifesting as a solitary retinal lesion. There have been a few cases of retinal astrocytoma reported in infants and young children without evidence of tuberous sclerosis,6,7,9 –11,13,14,17,18 but we caution that longer follow-up for other manifestations of tuberous sclerosis in the first 1 or 2 decades of life would be important in such cases (Table 1). Our cases, however, are similar to other reported cases of adults 8,12,16 with solitary retinal astrocytoma unassociated with tuberous sclerosis. Unlike the astrocytic hamartoma of tuberous sclerosis, the presumed acquired astrocytoma is more aggressive and lacks clinical evidence of calcium. Therefore, it seems to be a different type of glial tumor. The progressive growth of retinal astrocytoma is similar to that of low-grade astrocytoma of the brain. In the brain, these tumors are seen in young patients at a mean age of 27 years as a diffuse or circumscribed mass, showing little response to radiation.29 The affected patients often have a long history of symptoms. Despite the benign cytology, low-grade brain astrocytomas are progressive, and recurrence after resection is common, leading to only 25% survival at 10 years.30 In summary, we present 2 patients, a teenager and an adult, each with a rare retinal tumor, histopathologically proven to be a retinal astrocytoma. We suggest that they represent acquired lesions, unassociated with tuberous sclerosis and similar to the brain astrocytoma. They both
showed progressive enlargement and associated findings such as vitreous hemorrhage, vitreous seeding, and exudative retinal detachment. This tumor should be differentiated from intraocular malignancy, particularly retinoblastoma and choroidal melanoma.
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Figure 2. A 35-year-old woman with an amelanotic macular tumor and total retinal detachment. A, July 1984. The amelanotic tumor is seen deep to the retinal vessels and overhangs the optic disc. B, July 1984. Fluorescein angiogram, arterial phase. Prominent intrinsic vessels are seen within the mass. C, July 1984. Fluorescein angiogram, late phase. Diffuse hyperfluorescence of the tumor is noted. D, July 1984. Ocular ultrasonography, B scan. The nodular echogenic mass and retinal detachment are visualized. E, July 1984. Low-power microscopy of the enucleated globe demonstrates the mass arising from the juxtapapillary retina and prepapillary region. Note the subretinal fluid (stain, hematoxylin– eosin; original magnification, ⫻4). F, July 1984. High-power microscopy reveals fascicles of bland spindle cells with round or slightly elongated basophilic vacuolated nuclei consistent with the diagnosis of astrocytoma (stain, hematoxylin– eosin; original magnification, ⫻100).
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