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Atypical Retinal Astrocytic Hamartoma Diagnosed by Fine-needle Biopsy
Atypical Retinal Astrocytic Hamartoma Diagnosed by Fine' needle Biopsy Jerry A. Shields, MD,1.2 Carol L. Shields, MD,I ,2 Hormoz Ehya, MD,3 Edward Buckley, MD,'" Patrick De Potter, MDl,2 Background: Retinal astrocytic hamartoma and retinoblastoma may be very similar clinically, and their differentiation in atypical cases can be difficult, even with the use of ancillary methods such as fluorescein angiography, ultrasonography, and computed tomography. To the authors' knowledge, fine-needle aspiration biopsy has not been used to diagnose astrocytic hamartoma in such cases. Patients and Methods: A 7-week-old boy had a minimally calcified retinal mass in the macular area of the left eye associated with an extensive secondary retinal detachment. The differential diagnosis included retinal astrocytic hamartoma and retinoblastoma. A transvitreal fine-needle aspiration biopsy was performed. Results: The cytology of the needle biopsy showed benign spindle and stellate cells, which were compatible with glial cells. The lesion had immunoreactivity for glial fibrillary acidic protein, further supporting the diagnosis of astrocytic tumor. Conclusion: Fine-needle aspiration biopsy is diagnostically useful in unusual cases where the differential diagnosis between retinoblastoma and astrocytic hamartoma is difficult. Ophthalmology 1996; 103:949-952
Retinoblastoma is a malignant intraocular neoplasm of childhood that generally has characteristic clinical features. 1 Retinal astrocytic hamartoma, often associated with tuberous sclerosis, is a benign hamartoma that can clinically resemble retinoblastoma. 2 Although these two tumors generally have subtle features that serve to differentiate them, in some instances they may be remarkably similar. 3 We evaluated a patient in whom a fundus mass
was ophthalmoscopically compatible with retinoblastoma but astrocytic hamartoma was also a diagnostic possibility. Because a definitive diagnosis could not be made with more standard methods, a transocular fine-needle aspiration biopsy (FNAB) was performed.4 Cytologic assessment of the biopsy specimen confirmed the diagnosis of astrocytic hamartoma.
Case Report Originally received: August 25, 1995. Revision accepted: March 13, 1996. lOcular Oncology Service, Wills Eye Hospital, Philadelphia. 2 Department of Ophthalmology, Thomas Jefferson University, Philadelphia. 3 Department of Pathology, Fox Chase Cancer Center, Philadelphia. 4 Department of Ophthalmology, Duke University Medical Center, Durham. Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania. The authors have no proprietary interest in any of the materials used iri this study. Reprint requests to Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.
A 7-week-old boy had leukocoria and possible retinoblastoma in the left eye. His mother had undergone computed tomography (CT) that showed a small focus of cerebral calcification. The CT scan had been performed because the mother's sister and her son had had seizures, intracranial hamartomas, and cutaneous lesions suggestive of tuberous sclerosis. Their ocular fundi were reportedly normal. Ultrasonography and CT scan of our patient showed an ovoid retinal mass that demonstrated a small focus of calcification. No intracranial lesions were found. The diagnosis was probable retinoblastoma, and enucleation was being considered. The child was referred to the Ocular Oncology Service for another opinion. Results of our examination showed that the child had no cutaneous lesions of tuberous sclerosis. The right eye was essen-
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Shields et al . Atypical Retinal Astrocytic Hamartoma Figure 1. Fundus photograph of a macular tumor in the left eye. The extensive secondary retinal detachment cannot be visualized in the photograph. Figure 2. Fluorescein angiography. A, full venous phase shows vascularity of the tumor. B, late phase shows intense staining of the tumor. Figure 3. Ultrasonography. A, A-scan shows high internal reflectivity in the tumor. B, B-scan shows acoustic solidity of a retinal mass. Figure 4. Cytology of fine-needle aspiration biopsy specimen. A, a cohesive group of spindle- and stellate-shaped tumor cells with small bland nuclei (Papanicolaou stain; original magnification, X600). B, a group of tumor cells show positive staining for glial fibrillary acidic protein (original magnification, X 1(00).
tially normal, with no retinal tumors. Results of fundus examination of the left eye disclosed a yellow-white macular mass, measuring 8 X 8 mm in diameter and 3 mm in thickness (Fig 1). A secondary retinal detachment extended to the equator for 360°. Fluorescein angiography disclosed that the mass filled rapidly in the arterial phase, showed progressive leakage, and stained intensely in the late angiograms (Fig 2). A-scan ultrasonography showed that the mass had high internal reflectivity, and B-scan showed it to be acoustically solid with no distinct foci of calcification (Fig 3). Although the fundus mass most closely resembled retinoblastoma, the family history of tuberous sclerosis raised the possibility that the lesion was an atypical astrocytic hamartoma. Based on ophthalmoscopy, fluorescein angiography, and ultrasonography, we could not decide whether the lesion was retinoblastoma or astrocytic hamartoma. The parents were advised of all options, and they elected to have us perform a transocular FNAB.4 Using indirect ophthalmoscopy, the biopsy was performed by passing a 25-gauge needle through the pars plana and vitreous cavity and into the mass. Other than a focal, transient vitreous hemorrhage at the biopsy site, there were no complications. The aspirated material was collected in 4 ml of a balanced salt solution and was fixed in an equal volume of 50% ethanol. Cytologic preparations were made by cytocentrifugation technique, and the smears were stained by the Papanicolaou method. Additional preparations were stained by immunoperoxidase method with antibodies against cytokeratin, vimentin, and glial fibrillary acidic protein. The smears contained numerous cells, some single and many in cohesive groups. The cells had abundant cytoplasm and varied in shape from spindle to stellate forms (Fig 4A). The nuclei were small and mostly round to oval, and some were cigar-shaped. The chromatin was finely granular and evenly dispersed. Hyperchromasia, prominent nucleoli, and mitoses were not observed. There were no inflammatory cells or necrosis. The cytologic features were compatible with glial tissue. The cells had immunoreactivity for vimentin and glial fibrillary acidic protein (Fig 4B). No staining for cytokeratin was observed. These cytologic findings were consistent with a diagnosis of astrocytic hamartoma, and immunohistochemical findings supported that diagnosis. Therefore, observation was advised. Two months later, the tumor was unchanged in size and the retinal detachment had almost entirely resolved. Nine months after the biopsy, the retinal detachment was gone and the previously solid lesion had transformed into a translucent cystic mass that was evident with both ophthalmoscopy and ultrasonography.
Discussion An astrocytic tumor of the retina can occur as a solitary or multifocal astrocytic hamartoma, often associated with
tuberous sclerosis, or it can occur as a solitary acquired tumor, not associated with tuberous sclerosis.2 The retinal astrocytic hamartoma found in patients with tuberous sclerosis characteristically occurs in children, is nonprogressive, often calcified, and does not usually produce a significant retinal detachment. In most patients, retinoblastoma can be differentiated from retinal astrocytic hamartoma by subtle ophthalmoscopic differences. Retinoblastoma is more likely to have dilated tortuous retinal feeder vessels, secondary retinal detachment, tumor seeds in the subretinal space and vitreous, and chalky white calcification. In addition, it is progressive. Astrocytic hamartoma generally is not associated with widely dilated feeder vessels, retinal detachment, or tumor seeding. The calcification in astrocytic hamartoma is more often glistening yellow rather than chalky white, and the tumor is usually nonprogressive. 2 However, in atypical cases, the differentiation between these tumors can be exceedingly difficult. Ancillary studies may be of variable assistance in the differentiation between these two conditions. Fluorescein angiography of retinoblastoma generally shows prompt and progressive hyperfluorescence of the mass with intense late staining. Fluorescein angiography of astrocytic hamartoma generally shows slightly more delayed hyperfluorescence but similar late hyperfluorescence of the lesion. 2 Ultrasonography and CT are not particularly helpful in resolving small retinal lesions and both astrocytic hamartoma and retinoblastoma can have demonstrable calcification with these techniques. 5 In the patient reported here, ophthalmoscopy, fluorescein angiography, ultrasonography, and CT scan were of limited diagnostic help. Fine-needle aspiration biopsy was justified to establish the diagnosis because the lesion clinically resembled retinoblastoma, and enucleation was under consideration. If the lesion were a retinoblastoma, enucleation or radiotherapy would be the most acceptable therapeutic options. If the lesion were an astrocytic hamartoma, then observation without active treatment would be the most reasonable option. Fine-needle aspiration biopsy appeared to be the best method of resolving this diagnostic dilemma, because the cytologic features of astrocytic hamartoma are different from those of retinoblastoma. 6 We do not recommend diagnostic FNAB in typical cases of retinoblastoma, because this friable tumor theoretically could be disseminated by such manipulation. 4 In the current case, we advised the parents of the options of observing the lesion for a period of time or performing FNAB; they requested that we do anything
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to rule out a malignancy as soon as possible. Therefore, FNAB was performed. Cytologic examination of the FNAB specimen demonstrated that the lesion was a benign astrocytic hamartoma, and no further treatment was advised. We are not aware of other cases of retinal astrocytic tumors in which a diagnosis had been made by FNAB. However, in an exceptional case with vitreous seeding, a diagnosis was reached by cytologic examination of a vitrectomy specimen. 7 The lesion in our patient has not progressed, and the secondary retinal detachment has resolved.
References 1. Shields JA, Shields CL. Retinoblastoma. Clinical and pathologic features. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders Co, 1993; 307-16.
2. Shields JA, Shields CL. Glial tumors of the retina and optic disc. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders Co, 1993; 422-7. 3. Drewe RH, Hiscott P, Lee WR. Solitary astrocytic hamartoma simulating retinoblastoma. Ophthalmologica 1985; 190: 158-67. 4. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology 1993; 100: 1677-84. 5. DePotter P, Shields JA, Shields CL. Tumors and pseudotumors of the retina. In: DePotter P, Shields JA, Shields CL, eds. MRI of the Eye and Orbit. Philadelphia; JB Lippincott Co, 1995; 93-8. 6. O'Hara BJ, Ehya H, Shields JA, et al. Fine needle aspiration biopsy in pediatric ophthalmic tumors and pseudotumors. Acta Cytologica 1993;37:125-30. 7. deJ uan E J r, Green WR, Gupta PK, Baranano EC. Vitreous seeding by astrocytic hamartoma in a patient with tuberous sclerosis. Retina 1984;4: 100-2.
Centennial Advertisement From Convention Bulletin, The Meyrowitz Manufacturing Co., 1902. Skeel Self-recording Perimeter, with color discs, pencils, and pad of 50 charts ($45.00).*
* Centennial advertisement provided courtesy of the Museum of Ophthalmology, Ophthalmology, San Francisco, California
952
Foundation of the American Academy of
Retinoblastoma is a malignant intraocular neoplasm of childhood that generally has characteristic clinical features. 1 Retinal astrocytic hamartoma, often associated with tuberous sclerosis, is a benign hamartoma that can clinically resemble retinoblastoma. 2 Although these two tumors generally have subtle features that serve to differentiate them, in some instances they may be remarkably similar. 3 We evaluated a patient in whom a fundus mass
was ophthalmoscopically compatible with retinoblastoma but astrocytic hamartoma was also a diagnostic possibility. Because a definitive diagnosis could not be made with more standard methods, a transocular fine-needle aspiration biopsy (FNAB) was performed.4 Cytologic assessment of the biopsy specimen confirmed the diagnosis of astrocytic hamartoma.
Case Report Originally received: August 25, 1995. Revision accepted: March 13, 1996. lOcular Oncology Service, Wills Eye Hospital, Philadelphia. 2 Department of Ophthalmology, Thomas Jefferson University, Philadelphia. 3 Department of Pathology, Fox Chase Cancer Center, Philadelphia. 4 Department of Ophthalmology, Duke University Medical Center, Durham. Supported by the Eye Tumor Research Foundation, Philadelphia, Pennsylvania. The authors have no proprietary interest in any of the materials used iri this study. Reprint requests to Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.
A 7-week-old boy had leukocoria and possible retinoblastoma in the left eye. His mother had undergone computed tomography (CT) that showed a small focus of cerebral calcification. The CT scan had been performed because the mother's sister and her son had had seizures, intracranial hamartomas, and cutaneous lesions suggestive of tuberous sclerosis. Their ocular fundi were reportedly normal. Ultrasonography and CT scan of our patient showed an ovoid retinal mass that demonstrated a small focus of calcification. No intracranial lesions were found. The diagnosis was probable retinoblastoma, and enucleation was being considered. The child was referred to the Ocular Oncology Service for another opinion. Results of our examination showed that the child had no cutaneous lesions of tuberous sclerosis. The right eye was essen-
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48
Shields et al . Atypical Retinal Astrocytic Hamartoma Figure 1. Fundus photograph of a macular tumor in the left eye. The extensive secondary retinal detachment cannot be visualized in the photograph. Figure 2. Fluorescein angiography. A, full venous phase shows vascularity of the tumor. B, late phase shows intense staining of the tumor. Figure 3. Ultrasonography. A, A-scan shows high internal reflectivity in the tumor. B, B-scan shows acoustic solidity of a retinal mass. Figure 4. Cytology of fine-needle aspiration biopsy specimen. A, a cohesive group of spindle- and stellate-shaped tumor cells with small bland nuclei (Papanicolaou stain; original magnification, X600). B, a group of tumor cells show positive staining for glial fibrillary acidic protein (original magnification, X 1(00).
tially normal, with no retinal tumors. Results of fundus examination of the left eye disclosed a yellow-white macular mass, measuring 8 X 8 mm in diameter and 3 mm in thickness (Fig 1). A secondary retinal detachment extended to the equator for 360°. Fluorescein angiography disclosed that the mass filled rapidly in the arterial phase, showed progressive leakage, and stained intensely in the late angiograms (Fig 2). A-scan ultrasonography showed that the mass had high internal reflectivity, and B-scan showed it to be acoustically solid with no distinct foci of calcification (Fig 3). Although the fundus mass most closely resembled retinoblastoma, the family history of tuberous sclerosis raised the possibility that the lesion was an atypical astrocytic hamartoma. Based on ophthalmoscopy, fluorescein angiography, and ultrasonography, we could not decide whether the lesion was retinoblastoma or astrocytic hamartoma. The parents were advised of all options, and they elected to have us perform a transocular FNAB.4 Using indirect ophthalmoscopy, the biopsy was performed by passing a 25-gauge needle through the pars plana and vitreous cavity and into the mass. Other than a focal, transient vitreous hemorrhage at the biopsy site, there were no complications. The aspirated material was collected in 4 ml of a balanced salt solution and was fixed in an equal volume of 50% ethanol. Cytologic preparations were made by cytocentrifugation technique, and the smears were stained by the Papanicolaou method. Additional preparations were stained by immunoperoxidase method with antibodies against cytokeratin, vimentin, and glial fibrillary acidic protein. The smears contained numerous cells, some single and many in cohesive groups. The cells had abundant cytoplasm and varied in shape from spindle to stellate forms (Fig 4A). The nuclei were small and mostly round to oval, and some were cigar-shaped. The chromatin was finely granular and evenly dispersed. Hyperchromasia, prominent nucleoli, and mitoses were not observed. There were no inflammatory cells or necrosis. The cytologic features were compatible with glial tissue. The cells had immunoreactivity for vimentin and glial fibrillary acidic protein (Fig 4B). No staining for cytokeratin was observed. These cytologic findings were consistent with a diagnosis of astrocytic hamartoma, and immunohistochemical findings supported that diagnosis. Therefore, observation was advised. Two months later, the tumor was unchanged in size and the retinal detachment had almost entirely resolved. Nine months after the biopsy, the retinal detachment was gone and the previously solid lesion had transformed into a translucent cystic mass that was evident with both ophthalmoscopy and ultrasonography.
Discussion An astrocytic tumor of the retina can occur as a solitary or multifocal astrocytic hamartoma, often associated with
tuberous sclerosis, or it can occur as a solitary acquired tumor, not associated with tuberous sclerosis.2 The retinal astrocytic hamartoma found in patients with tuberous sclerosis characteristically occurs in children, is nonprogressive, often calcified, and does not usually produce a significant retinal detachment. In most patients, retinoblastoma can be differentiated from retinal astrocytic hamartoma by subtle ophthalmoscopic differences. Retinoblastoma is more likely to have dilated tortuous retinal feeder vessels, secondary retinal detachment, tumor seeds in the subretinal space and vitreous, and chalky white calcification. In addition, it is progressive. Astrocytic hamartoma generally is not associated with widely dilated feeder vessels, retinal detachment, or tumor seeding. The calcification in astrocytic hamartoma is more often glistening yellow rather than chalky white, and the tumor is usually nonprogressive. 2 However, in atypical cases, the differentiation between these tumors can be exceedingly difficult. Ancillary studies may be of variable assistance in the differentiation between these two conditions. Fluorescein angiography of retinoblastoma generally shows prompt and progressive hyperfluorescence of the mass with intense late staining. Fluorescein angiography of astrocytic hamartoma generally shows slightly more delayed hyperfluorescence but similar late hyperfluorescence of the lesion. 2 Ultrasonography and CT are not particularly helpful in resolving small retinal lesions and both astrocytic hamartoma and retinoblastoma can have demonstrable calcification with these techniques. 5 In the patient reported here, ophthalmoscopy, fluorescein angiography, ultrasonography, and CT scan were of limited diagnostic help. Fine-needle aspiration biopsy was justified to establish the diagnosis because the lesion clinically resembled retinoblastoma, and enucleation was under consideration. If the lesion were a retinoblastoma, enucleation or radiotherapy would be the most acceptable therapeutic options. If the lesion were an astrocytic hamartoma, then observation without active treatment would be the most reasonable option. Fine-needle aspiration biopsy appeared to be the best method of resolving this diagnostic dilemma, because the cytologic features of astrocytic hamartoma are different from those of retinoblastoma. 6 We do not recommend diagnostic FNAB in typical cases of retinoblastoma, because this friable tumor theoretically could be disseminated by such manipulation. 4 In the current case, we advised the parents of the options of observing the lesion for a period of time or performing FNAB; they requested that we do anything
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to rule out a malignancy as soon as possible. Therefore, FNAB was performed. Cytologic examination of the FNAB specimen demonstrated that the lesion was a benign astrocytic hamartoma, and no further treatment was advised. We are not aware of other cases of retinal astrocytic tumors in which a diagnosis had been made by FNAB. However, in an exceptional case with vitreous seeding, a diagnosis was reached by cytologic examination of a vitrectomy specimen. 7 The lesion in our patient has not progressed, and the secondary retinal detachment has resolved.
References 1. Shields JA, Shields CL. Retinoblastoma. Clinical and pathologic features. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders Co, 1993; 307-16.
2. Shields JA, Shields CL. Glial tumors of the retina and optic disc. In: Shields JA, Shields CL, eds. Intraocular Tumors. A Text and Atlas. Philadelphia: WB Saunders Co, 1993; 422-7. 3. Drewe RH, Hiscott P, Lee WR. Solitary astrocytic hamartoma simulating retinoblastoma. Ophthalmologica 1985; 190: 158-67. 4. Shields JA, Shields CL, Ehya H, et al. Fine needle aspiration biopsy of suspected intraocular tumors. The 1992 Urwick Lecture. Ophthalmology 1993; 100: 1677-84. 5. DePotter P, Shields JA, Shields CL. Tumors and pseudotumors of the retina. In: DePotter P, Shields JA, Shields CL, eds. MRI of the Eye and Orbit. Philadelphia; JB Lippincott Co, 1995; 93-8. 6. O'Hara BJ, Ehya H, Shields JA, et al. Fine needle aspiration biopsy in pediatric ophthalmic tumors and pseudotumors. Acta Cytologica 1993;37:125-30. 7. deJ uan E J r, Green WR, Gupta PK, Baranano EC. Vitreous seeding by astrocytic hamartoma in a patient with tuberous sclerosis. Retina 1984;4: 100-2.
Centennial Advertisement From Convention Bulletin, The Meyrowitz Manufacturing Co., 1902. Skeel Self-recording Perimeter, with color discs, pencils, and pad of 50 charts ($45.00).*
* Centennial advertisement provided courtesy of the Museum of Ophthalmology, Ophthalmology, San Francisco, California
952
Foundation of the American Academy of