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Simultaneous Intraocular and Orbital Non-Hodgkin Lymphoma in the Acquired Immune Deficiency Syndrome
Simultaneous Intraocular and Orbital Non--Hodgkin Lymphoma in the Acquired Immune Deficiency Syndrome Dennis C. Matzkin, MD,1 Thomas L. Slamovits, MD,I,2 Pearl S. Rosenbaum, MD1,3 Background: Non-Hodgkin lymphoma is more common in patients with the acquired immune deficiency syndrome (AIDS), and the incidence of non-Hodgkin lymphoma in the AIDS population has been increasing as the life expectancy of these patients has increased. Nevertheless, intraocular lymphoma, as part of primary central nervous system lymphoma and orbital non-Hodgkin lymphoma, has rarely been reported in patients with AIDS. Co-existent intraocular and orbital lymphoma is exceptionally unusual. The clinical and histopathologic findings are reported in a patient with AIDS who had simultaneous intraocular and orbital non-Hodgkin lymphoma. The clinical funduscopic findings initially were attributed to a viral retinitis. Methods: A left orbital biopsy followed by enucleation of the left eye was performed and studied by light microscopy. Immunophenotyping of the orbital biopsy also was performed. Findings: Simultaneous intraocular and orbital large cell malignant lymphoma was present with neoplastic spread directly along the scleral canal of the ciliary nerve. Massive necrosis involving the retina, retinal pigment epithelium, choroid, and optic nerve, as well as several solid retinal pigment epithelial detachments, were observed. Immunophenotyping of the orbital tumor disclosed positive staining for Leu 4 (T cells, 30%) and Leu 14 (8 cells, 60%). Immunostaining for light and heavy chains was precluded by tumor necroSis. Conclusion: Non-Hodgkin lymphoma should be included in the differential diagnosis of acute retinitis, and proptosis in patients with AIDS. Ophthalmology 1994;101 :850-855
Originally received: May 25, 1993. Revision accepted: October 1, 1993. I Department of Ophthalmology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
2 Departments of Neurology and Neurosurgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
3 Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
Supported in part by an unrestricted grant to the Department of Ophthaln;lOlogy and Visual Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, from Research to Prevent Blindness, Inc., New York, New York. Reprint requests to Thomas L. Slamovits, MD, Department of Ophthalmology, Montefiore Medical Center/Albert Einstein College ofMedicine, 111 E 210th St, Bronx, NY 10467.
850
Various clinical syndromes of intraocular l - s and orbital lymphoma6- 8 as well as lymphomatous optic neuropathy9-14 have been described previously. Simultaneous intraocular and orbital lymphoma is distinctly unusual. IS - 17 The purpose of this report is to present the clinical and histopathologic findings in a patient with acquired immune deficiency syndrome (AIDS) who demonstrated simultaneous intraocular and orbital non-Hodgkin lymphoma.
Case Report A 71-year-old man presented to his ophthalmologist because of decreased vision in the left eye. His ophthalmic history was neg-
Matzkin et al . Non-Hodgkin Lymphoma in AIDS ative, but 8 years previously he had undergone coronary artery bypass surgery and received multiple blood transfusions. Two years previously, he underwent a partial laryngectomy followed by radiotherapy for carcinoma of the larynx. At the time of his ocular presentation, he had no known metastases. Results of initial ophthalmologic examination showed bestcorrected visual acuities of 20/25 in the right eye and 20/100 in the left. The anterior segments were unremarkable. In the right eye, a single flame-shaped retinal hemorrhage was present. In the left eye, the retinal vessels were dilated slightly and a few cells were noted in the posterior vitreous. Florid cystoid macular edema, confirmed on intravenous fluorescein angiography, was present on the left. The diagnosis was unclear but presumed to be a chronic retinal venous obstruction; no treatment was prescribed. One month later, vision in the left eye declined precipitously to hand motions and a left relative afferent pupillary defect was noted. In addition, the left eye had 3+ posterior vitreous cells as well as clumps of cells on the detached posterior hyaloid face ("pseudo-Keratic precipitates"). The left optic disc was markedly pale and swollen, with surrounding peripapillary hemorrhages and an area of retinitis extending into the papillomacular bundle (Fig I). Intravenous fluorescein angiography showed delayed arterial filling with a prolonged arteriovenous transit time in the left eye. There was marked leakage from the optic disc in the left eye. Results of the ophthalmoscopic examination were unchanged in the right eye. Based on the retinal findings, as well as a history of blood transfusion, a test for the human immunodeficiency virus (HIV) was performed and proved to be positive. The clinical impression was that of a cytomegalovirus (CMV) retinitis, and treatment was commenced with intravenous ganciclovir. Two weeks later, the patient complained of severe pain in the left eye. Results of repeat examination of the left eye showed vision of no light perception,S mm of axial proptosis, complete upper lid ptosis, and total ophthalmoplegia. The pupil was dilated and amaurotic. Corneal sensation was absent. The vitreous showed a cellular reaction, which precluded visualization of the posterior pole. The retinal periphery appeared diffusely ischemic and hemorrhagic. A computed tomographic (CT) scan disclosed an intraconal mass molding to the posterior sclera, extending to the apex of the orbit with cavernous sinus extension (Fig 2). Visual acuity in the right eye was 20/25, and results of the funduscopic examination were unremarkable. Results of systemic examination showed a well-nourished man without organomegaly or lymphadenopathy. Results of neurologic examination except for the left ocular abnormality, complete blood count, blood cultures and CMV titers, chest xray, bone marrow biopsy, lumbar puncture, and urine cultures for CMV failed to demonstrate a systemic opportunistic infection or neoplasm. A fine-needle aspiration biopsy of the left orbit disclosed large malignant-appearing lymphocytes. The diagnosis of large cell malignant lymphoma was confirmed subsequently on open orbital biopsy (Fig 3). Immunophenotyping of the tumor demonstrated positive staining for Leu 4 (T cells, 30% positive), and Leu 14 (B cells, 60% positive); however, staining for light and heavy chain monoclonality was precluded by extensive areas of tissue necrosis. Progressive proptosis, exposure keratopathy, and pain led to enucleation. A long segment of the optic nerve was resected with the globe but no attempt was made to debulk the posterior orbital component of the tumor. Results of histopathologic examination of the enucleated left globe demonstrated an acute necrotizing keratitis with ulceration and hypopyon formation, consistent with an exposure keratopathy due to progressive proptosis. An
associated trabeculitis and acute and chronic iridocyclitis also were seen. The vitreous was detached posteriorly and contained scattered neoplastic lymphocytes, melanophages, and degenerated inflammatory cells. There was massive necrosis ofthe retina, retinal pigment epithelium, choroid and optic nerve (Figs 4 and 5). Neoplastic infiltration was observed focally within the choroid, optic nerve sheath, outer scleral lamellae as well as along the scleral canal of the ciliary nerve (Fig 6). Occasional solid retinal pigment epithelial detachments were observed (Fig 7). No intranuclear or intracytoplasmic inclusion bodies were observed within the necrotic retina and choroid. Electron microscopy was not performed. The patient received postoperative radiation therapy to the left orbit. Ganciclovir was discontinued and azidothymidine recommenced when it became apparent that intraocular and orbitallymphoma, rather than CMV retinitis, was the likely cause for the retinopathy. After 19 months of follow-up, residual orbital tumor was evident on CT scan, but there was no evidence of intracranial or further extraorbital extension of systemic lymphoma. The right eye remained free of retinopathy. In addition, there were no signs of opportunistic infection or neoplasm in the right orbit and adnexa. The patient died approximately 21 months after documentation of HIV positivity, with no clinical evidence of systemic lymphoma. Postmortem examination was not performed.
Discussion The occurrence of non-Hodgkin lymphoma associated with AIDS has become well recognized since the first report in 1982.18 In 1985, the presence of a high grade nonHodgkin lymphoma in the setting of HIV positivity was added to the criteria for confirming the diagnosis of AIDS,19 and in 1987 intermediate grade non-Hodgkin lymphoma was added to the diagnostic criteria.2° Extended survival with prolonged immunosuppression and with substantial T4-cell depletion is probably an important factor in the development of these lymphomas. 21 Approximately 20% of patients with AIDS who are affected with non-Hodgkin lymphoma have extranodal involvement, especially in the central nervous system (CNS), compared with less than 1% in patients without AIDS who have non-Hodgkin lymphoma. 22 Non-Hodgkin lymphoma may present with two distinct clinical entities. The first form is primary lymphoma of the CNS (CNSnon-Hodgkin lymphoma), in which tumor may involve the brain parenchyma, meninges, intradural spinal cord, and the posterior segment of the eye. The intraocular lymphoma may be the presenting form of CNS-nonHodgkin lymphoma, antedating CNS or systemic disease by many months.4.23 Intraocular lymphoma associated with CNS-non-Hodgkin lymphoma, formerly referred to as reticulum cell sarcoma, is now referred to as ocular CNS-non-Hodgkin lymphoma. The second form of nonHodgkin lymphoma is systemic lymphoma which may involve the brain by infiltration of the ventricular space or compression of the spinal cord or its nerve roots from locations outside of the dura. Vision may be affected due to invasion of the orbit and only rarely by uveal metastasis. Intraocular lymphoma in immunocompetent patients may result in one of four different clinical forms. The
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most common is the ocular CNS form (reticulum cell sarcoma), producing characteristic multifocal infiltration of the retinal pigment epithelium appearing as solid detachments of the retinal pigment epithelium,24 as well as a PQsterior uveitis. The lymphoma may invade the overlying neurosensory retina and obscure the underlying pigment epithelial detachment, and the retinal whitening may be mistaken for a necrotizing retinitis. With neoplastic infiltration of the inner retina, capillary damage and intraretinal hemorrhage may occur. Thus, there may be areas of necrosis, whitening, and hemorrhage, simulating retinal necrosis as seen in retinitis associated with herpes simplex, herpes zoster, CMV, or toxoplasmosis. 25 Another form of systemic or metastatic non-Hodgkin lymphoma without CNS involvement is associated with lymphomatous infiltration, occurring predominantly in the anterior uveal tract2 6 simulating iridocyclitis,25 or posteriorly resembling fundus flavimaculatusY Other more unusual ocular lymphomatoses include angioendotheliomatosis28 and reactive lymphoid hyperplasia of the uveal tract,29 the latter of which may represent a low-grade B-celllymphoma. 3o Human T-celllymphotropic virus type 1 (HLTV-l) is a known cause of adult T-cell leukemia/lymphoma, and both orbital 31 and intraocular lymphoma have rarely been described in patients infected with HLTV-1. Rao (unpublished data; presented at the Verhoeff Society Meeting, Miami, April 1993) described a patient with HLTV-l who had intraocular lymphoma diagnosed by chorioretinal biopsy. Clinically, the patient was found to have multifocal flat subretinal pale lesions measuring approximately 100 Jim in diameter, increasing in size over time. Histopathologically, lymphomatous infiltration was evident focally within the retina as well as within the subretinal pigment epithelial space. The risk for the development of CNS-non-Hodgkin lymphoma in patients with AIDS has been estimated to be 100 times that of immunocompetent patients. 32,33 In patients with AIDS, the disease has a tendency to be of a
high-grade malignancy with a poor prognosis. Despite the increasing incidence oflymphoma in patients with AIDS, relatively few reports in the literature have documented either intraocular25 ,34,35 or orbital 36-4o lymphoma in this group of patients. Schanzer et al 35 reported a case of a 42-year-old man with HIV who had retinochoroidal lesions in both eyes. The diagnosis of ocular CNS-non-Hodgkin lymphoma was made on a vitrectomy specimen. A spinal fluid cytologic specimen subsequently was positive for lymphoma, and neuroimaging studies showed an asymptomatic lesion in the cerebellum. Gass and Trattler,25 in their report of an immunocompetent patient with ocular lymphoma who had a retinal branch vein occlusion, mentioned a patient with AIDS who had an acute branch retinal arterial occlusion associated with a solid retinal pigment epithelial detachment and retinal infiltration. Magnetic imaging of the brain demonstrated lymphoma which was later confirmed by brain biopsy. The ocular mass was presumed to be lymphoma, which subsequently resolved after radiotherapy. Stanton et al 34 reported an autopsy proven case of primary bilateral intraocular CNS lymphoma in a patient with AIDS. In this case, results of histopathologic examination of the eyes disclosed the bulk of the tumor beneath the retinal pigment epithelium and the subretinal space. In addition, there was lymphomatous infiltration of all layers of the retina. Bruch's membrane was intact, and there was no invasion of the choroid. In addition, no tumor cells were seen in the optic nerve or in the subarachnoid space of the nerve sheath although the brain parenchyma, and the overlying leptomeninges were diffusely involved. Orbital lymphoma is also recognized as a site of extranodal disease, and may present primarily with an orbital mass in 1.0% to 2.4% of cases. 7,8 A few cases of orbital lymphoma have been reported in the context of AIDS. Ziegler et al 18 and Brooks et al40 each reported a case of orbital Burkitt-like lymphoma associated with AIDS. In the case of Brooks et aI, the patient had a 2 lh-year history of a right upper lid swelling. On
) Top left, Figure 1. Fundus photograph of the left eye demonstrates marked disc elevation, peripapillary hemorrhage, and retinitis involving the posterior pole. Top right, Figure 2. Axial computed tomographic scan discloses an irregularly shaped solid mass along the intraorbital course of the left optic nerve. The tumor molds to the posterior aspect of the globe and extends into the left cavernous sinus. Second row left, Figure 3. Biopsy of the left orbit shows large neoplastic lymphocytes with pleomorphic, convoluted nuclei and prominent nucleoli (hematoxylin-eosin; original magnification, X160). Second row right, Figure 4. Massive thickening and necrosis of the retina, retinal pigment epithelium, and choroid. The inner-limiting membrane of the retina (arrowheads) and Bruch's membrane are intact (curved arrow). Scattered, viable neoplastic lymphoma cells are present within the choroid (hematoxylin-eosin; original magnification, XlO). Third row left, Figure 5. Low-power view of the posterior pole demonstrates extensive necrosis of the retina, retinal pigment epithelium, choroid, optic nerve, and nerve sheath (hematoxylin-eosin; original magnification, X5). Bottom right, Figure 6. The scleral canal of the ciliary nerve (asterisk) is surrounded by a lymphomatous infiltrate (L) as well as zones of necrosis (N) (hematoxylin-eosin; original magnification, X12.5). Bottom left, Figure 7. Detachment of necrotic retinal pigment epithelium (arrowheads) overlying a mound of necrotic cells and cellular debris. The underlying choroid is diffusely infiltrated by lymphocytes, plasma cells, and lymphoma cells (hematoxylin-eosin; original magnification, X63).
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CT scan, the mass involved the upper eyelid with posterior extension superiorly and laterally to the apex of the orbit, with inferior displacement of the globe. In an autopsy series, Jabs et al 38 reported one case of orbital lymphoma in a patient with AIDS, without providing any details of the case. Antle et a1 3? reported a case of large cell orbital non-Hodgkin lymphoma associated with AIDS that involved the superomedial orbit. Mansour39 reported a similar case involving the medial orbit that infiltrated the ethmoid sinus. The disease progressed slowly in both of these patients, as is typical of primary orbital lymphoma. Turok and Meyer36 reported a case of non-Hodgkin lymphoma involving the medial orbit that behaved more aggressively than the other reported cases, rapidly displacing, rather than molding to, the globe. Although the conjunctiva, eyelid, lacrimal gland, and orbital muscles are the most frequent periocular tissues involved with orbital lymphoma, the optic nerve may rarely be involved in Hodgkin l2 ,14 or non-Hodgkin lymphoma.9.10.11 ,13 No case of lymphomatous optic neuropathy has been reported in a patient with AIDS. McGavic l5 and Heath l6 reported a combined total of four cases of simultaneous orbital and intraocular lymphoma. Details of these cases, however, are incomplete. Trudeau et al,17 in a review of 87 cases of intraocular lymphoma, report one case of presumed intraocular lymphoma, with simultaneous bilateral optic nerve enlargement on CT. Lymphomatous infiltration of the optic nerves was diagnosed from tissue obtained at the time of Omaya reservoir insertion, but no intraocular specimen was obtained to confirm intraocular lymphoma in this patient. Our patient is unusual, in that he had simultaneous intraocular and orbital lymphoma. Although it is speculative whether the lymphoma occurred primarily within the globe or in the orbit, tumor along the scleral canal of the ciliary nerve suggests contiguous neoplastic spread (Fig 6). Clinically, the patient had retinal findings which might suggest that the non-Hodgkin lymphoma was initially intraocular. The funduscopic findings, namely cystoid macular edema and venous congestion, are an unusual presentation of ocular CNS-non-Hodgkin lymphoma which more typically presents with a posterior vitritis and solid retinal pigment epithelial detachments as described by Gass et al. 24 It is possible that the funduscopic features were secondary to lymphomatous compression at the level of the central retinal vein, due to orbital lymphoma or lymphoma involving the meningeal sheath of the optic nerve. A swollen optic nerve and retinopathy resembling CMV infection subsequently developed; however, this diagnosis was in question when no clinical response to ganciclovir therapy was obtained, The swollen optic nerve and retinopathy could have resulted from lymphomatous infiltration of the optic nerve and retina, or ischemia secondary to neoplastic vascular occlusion, or both. Profound orbital signs developed over the course of weeks, resulting in an orbital apex syndrome. On CT scan,
854
the bulk of the tumor was within the orbit, which might suggest that the tumor arose from within the orbit. However, results of histopathologic examination of the enucleated left globe showed malignant cells within intrascleral canals of the ciliary nerves, which suggests that the intraocular and orbital tumors did not arise independently but rather that there was contiguous spread via this interconnecting pathway. Orbital lymphoma typically molds rather than invades tissues, and may cause proptosis by mass effect. A rapidly growing orbital lymphoma has been shown to grossly displace the globe in a patient with AIDS.38 In our patient, the orbital tumor behaved aggressively and displaced the globe anteriorly. Conceivably, the aggressive nature of this tumor might have enabled it to invade the emissary channels, giving rise to secondary intraocular lymphoma. There was no evidence of systemic spread over the course of this patient's 21-month illness, and although no postmortem examination was obtained, we presume that no metastatic disease or extraorbitallymphoma was present. In summary, this patient had simultaneous intraocular and orbital lymphoma with neoplastic spread directly along the scleral canal of the ciliary nerve. Either the orbit or the globe served as the primary site of tumor. While the incidence of lymphoma in patients with AIDS appears to be rising, orbital and intraocular lymphoma is still a rare occurrence, and their co-existence is exceptional. Nevertheless, because lymphoma may masquerade as an intraocular opportunistic infection or orbital inflammatory disease, it behooves all ophthalmologists treating patients with AIDS to be aware of the various clinical presentations of non-Hodgkin lymphoma, and to consider lymphoma in the differential diagnosis of both orbital and intraocular disease, even in the absence of intracranial lymphoma.
References I. Givner I. Malignant lymphoma with ocular involvement. A clinico-pathologic report. Am J OphthalmoI1955;39:2932. 2. Gass IDM. Differential Diagnosis of Intraocular Tumors: A Stereoscopic Presentation. Saint Louis: CV Mosby, 1974;145. 3. Klingele TG, Hogan MI. Ocular reticulum cell sarcoma. Am J Ophthalmol 1975;79:39-47. 4. Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987;94:1631-9. 5. Guyer DR, Green WR, Schachat AP, et al. Bilateral ischemic optic neuropathy and retinal vascular occlusions associated with lymphoma and sepsis. Clinicopathologic correlation. Ophthalmology 1990;97:882-8. 6. Fitzpatrick PJ, Macko S. Lymphoreticular tumors of the orbit. Int J Radiat Oncol Bioi Phys 1984;10:333-40. 7. Reddy EK, Bhatia P, Evans RG. Primary orbitallymphomas. Int J Radiat Oncol Bioi Phys 1988;15:1239-41. 8. Lazzarino M, Morra E, Rosso R, et al. Clinicopathologic and immunologic characteristics of non-Hodgkin's lymphomas presenting in the orbit. Cancer 1985;55:1907-12.
Matzkin et al . Non-Hodgkin Lymphoma in AIDS 9. Yen M-Y, Liu J-H. Malignant lymphoma involving the optic nerve head and the retina. Ann Ophthalmol 1985;17:697700. 10. Kattah JC, Suski ET, Killen JY, et al. Optic neuritis and systemic lymphoma. Am J Ophthalmol 1980;89:431-6. 11. Kraus AM, O'Rourke J. Lymphomatous optic neuritis. Arch OphthalmoI1963;70:173-5. 12. Miller NR, Iliff WJ. Visual loss as the initial symptom in Hodgkin disease. Arch Ophthalmol 1975;93:1158-61. 13. Walsh FB, Shewmake BJ. An unusual case of reticulum cell sarcoma. Am J Ophthalmol 1972;74:741-3. 14. Litvak L, Leder MM, Kauvar AJ. Case reports. Hodgkin's disease involving optic nerve and brain. J Neurosurg 1964;21 :798-80 1. 15. McGavic JS. Lymphomatoid diseases involving the eye and its adnexa. Arch Ophthalmol 1943;30: 179-93. 16. Heath P. Ocular lymphomas. Trans Am Ophthalmol Soc 1948;46:385-98. 17. Trudeau M, Shepherd FA, Blackstein ME, et al. Intraocular lymphoma: report of three cases and review of the literature. Am J Clin Oncol 1988;11:126-30. 18. Ziegler JL, Drew WL, Miner RC, et al. Outbreak of Burkitt'slike lymphoma in homosexual men. Lancet 1982;2:631-3. 19. Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting-United States. MMWR Morb Mortal Wkly Rep 1985;34:373-5. 20. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR Morb Mortal Wkly Rep 1987;36:suppl 1. 21. Pluda JM, Yarchoan R, Jaffe ES, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on longterm antiretroviral therapy. Ann Intern Med 1990;113:27682. 22. Haskal ZJ, Lindan CE, Goodman Pc. Lymphoma in the immunocompromised patient. Radiol Clin North Am 1990;28:885-99. 23. Rosenbaum TJ, MacCarty CS, Buettner H. Uveitis and cerebral reticulum-cell sarcoma (large-cell lymphoma). Case report. J Neurosurg 1979;50:660-4. 24. Gass JDM, Sever RJ, Grizzard WS, et aI. Multifocal pigment epithelial detachments by reticulum cell sarcoma. A characteristic funduscopic picture. Retina 1984;4: 135-43. 25. Gass JDM, TrattIer HL. Retinal artery obstruction and atheromas associated with non-Hodgkin's large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 1991;109: 1134-9.
26. Barr CC, Green WR, Payne JW, et al. Intraocular reticulumcell sarcoma: c1inico-pathologic study of four cases and review of the literature. Surv Ophthalmol 1975;19: 224-39. 27. Gass JDM, Weleber RG, Johnson DR. Non-Hodgkin's lymphoma causing fundus picture simulating fundus flavimaculatus. Retina 1987;7:209-14. 28. Elner VM, Hidayat AA, Charles HC, et al. Neoplastic angioendotheliomatosis. A variant of malignant lymphoma immunohistochemical and ultrastructural observations of three cases. Ophthalmology 1986;93: 1237-45. 29. Gass JDM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 3rd ed. Vol. 1. St. Louis: CV Mosby, 1987:156-7. 30. Zimmerman LE. Discussion, 1638-9. Of: Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987;94: 1631-9. 31. Lauer SA, Fischer J, JonesJ, et al. Orbital T-cell lymphoma in human T-cell leukemia virus-I infection. Ophthalmology 1988;95: 110-15. 32. Hochberg FH, Loeffler JS, Prados M. The therapy of primary brain lymphoma. J Neurooncol 1991; 10: 191-201. 33. So YT, Choucair A, Davis RL, et aI. Neoplasms ofthe central nervous system in acquired immunodeficiency syndrome. In: Rosenblum ML, Levy RM, Bredesen DE, eds. AIDS and the Nervous System. New York: Raven Press, 1988, chap. 13. 34. Stanton CA, Sloan B III, Slusher MM, Greven CM. Acquired immunodeficiency syndrome-related primary intraocular lymphoma. Arch Ophthalmol 1992; 110: 1614-17. 35. Schanzer MC, Font RL, O'Malley RE. Primary ocular malignant lymphoma associated with the acquired immune deficiency syndrome. Ophthalmology 1991 ;98:88-91. 36. Turok DI, Meyer DR. Orbital lymphoma associated with acquired immunodeficiency syndrome. Arch Ophthalmol 1992; 110:610-11. 37. Antle CM, White VA, Horsman DE, Rootman J. Large cell orbital lymphoma in a patient with acquired immune deficiency syndrome. Case report and review. Ophthalmology 1990;97: 1494-8. 38. Jabs DA, Green WR, Fox R, et al. Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989;96: 1092-9. 39. Mansour AM. Orbital findings in acquired immunodeficiency syndrome [letter]. Am J OphthalmoI1990;110:7067. 40. Brooks HL Jr, Downing J, McClure JA, Engel HM. Orbital Burkitt's lymphoma in a homosexual man with acquired immune deficiency. Arch Ophthalmol 1984;102:1533-7.
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Originally received: May 25, 1993. Revision accepted: October 1, 1993. I Department of Ophthalmology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
2 Departments of Neurology and Neurosurgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
3 Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.
Supported in part by an unrestricted grant to the Department of Ophthaln;lOlogy and Visual Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, from Research to Prevent Blindness, Inc., New York, New York. Reprint requests to Thomas L. Slamovits, MD, Department of Ophthalmology, Montefiore Medical Center/Albert Einstein College ofMedicine, 111 E 210th St, Bronx, NY 10467.
850
Various clinical syndromes of intraocular l - s and orbital lymphoma6- 8 as well as lymphomatous optic neuropathy9-14 have been described previously. Simultaneous intraocular and orbital lymphoma is distinctly unusual. IS - 17 The purpose of this report is to present the clinical and histopathologic findings in a patient with acquired immune deficiency syndrome (AIDS) who demonstrated simultaneous intraocular and orbital non-Hodgkin lymphoma.
Case Report A 71-year-old man presented to his ophthalmologist because of decreased vision in the left eye. His ophthalmic history was neg-
Matzkin et al . Non-Hodgkin Lymphoma in AIDS ative, but 8 years previously he had undergone coronary artery bypass surgery and received multiple blood transfusions. Two years previously, he underwent a partial laryngectomy followed by radiotherapy for carcinoma of the larynx. At the time of his ocular presentation, he had no known metastases. Results of initial ophthalmologic examination showed bestcorrected visual acuities of 20/25 in the right eye and 20/100 in the left. The anterior segments were unremarkable. In the right eye, a single flame-shaped retinal hemorrhage was present. In the left eye, the retinal vessels were dilated slightly and a few cells were noted in the posterior vitreous. Florid cystoid macular edema, confirmed on intravenous fluorescein angiography, was present on the left. The diagnosis was unclear but presumed to be a chronic retinal venous obstruction; no treatment was prescribed. One month later, vision in the left eye declined precipitously to hand motions and a left relative afferent pupillary defect was noted. In addition, the left eye had 3+ posterior vitreous cells as well as clumps of cells on the detached posterior hyaloid face ("pseudo-Keratic precipitates"). The left optic disc was markedly pale and swollen, with surrounding peripapillary hemorrhages and an area of retinitis extending into the papillomacular bundle (Fig I). Intravenous fluorescein angiography showed delayed arterial filling with a prolonged arteriovenous transit time in the left eye. There was marked leakage from the optic disc in the left eye. Results of the ophthalmoscopic examination were unchanged in the right eye. Based on the retinal findings, as well as a history of blood transfusion, a test for the human immunodeficiency virus (HIV) was performed and proved to be positive. The clinical impression was that of a cytomegalovirus (CMV) retinitis, and treatment was commenced with intravenous ganciclovir. Two weeks later, the patient complained of severe pain in the left eye. Results of repeat examination of the left eye showed vision of no light perception,S mm of axial proptosis, complete upper lid ptosis, and total ophthalmoplegia. The pupil was dilated and amaurotic. Corneal sensation was absent. The vitreous showed a cellular reaction, which precluded visualization of the posterior pole. The retinal periphery appeared diffusely ischemic and hemorrhagic. A computed tomographic (CT) scan disclosed an intraconal mass molding to the posterior sclera, extending to the apex of the orbit with cavernous sinus extension (Fig 2). Visual acuity in the right eye was 20/25, and results of the funduscopic examination were unremarkable. Results of systemic examination showed a well-nourished man without organomegaly or lymphadenopathy. Results of neurologic examination except for the left ocular abnormality, complete blood count, blood cultures and CMV titers, chest xray, bone marrow biopsy, lumbar puncture, and urine cultures for CMV failed to demonstrate a systemic opportunistic infection or neoplasm. A fine-needle aspiration biopsy of the left orbit disclosed large malignant-appearing lymphocytes. The diagnosis of large cell malignant lymphoma was confirmed subsequently on open orbital biopsy (Fig 3). Immunophenotyping of the tumor demonstrated positive staining for Leu 4 (T cells, 30% positive), and Leu 14 (B cells, 60% positive); however, staining for light and heavy chain monoclonality was precluded by extensive areas of tissue necrosis. Progressive proptosis, exposure keratopathy, and pain led to enucleation. A long segment of the optic nerve was resected with the globe but no attempt was made to debulk the posterior orbital component of the tumor. Results of histopathologic examination of the enucleated left globe demonstrated an acute necrotizing keratitis with ulceration and hypopyon formation, consistent with an exposure keratopathy due to progressive proptosis. An
associated trabeculitis and acute and chronic iridocyclitis also were seen. The vitreous was detached posteriorly and contained scattered neoplastic lymphocytes, melanophages, and degenerated inflammatory cells. There was massive necrosis ofthe retina, retinal pigment epithelium, choroid and optic nerve (Figs 4 and 5). Neoplastic infiltration was observed focally within the choroid, optic nerve sheath, outer scleral lamellae as well as along the scleral canal of the ciliary nerve (Fig 6). Occasional solid retinal pigment epithelial detachments were observed (Fig 7). No intranuclear or intracytoplasmic inclusion bodies were observed within the necrotic retina and choroid. Electron microscopy was not performed. The patient received postoperative radiation therapy to the left orbit. Ganciclovir was discontinued and azidothymidine recommenced when it became apparent that intraocular and orbitallymphoma, rather than CMV retinitis, was the likely cause for the retinopathy. After 19 months of follow-up, residual orbital tumor was evident on CT scan, but there was no evidence of intracranial or further extraorbital extension of systemic lymphoma. The right eye remained free of retinopathy. In addition, there were no signs of opportunistic infection or neoplasm in the right orbit and adnexa. The patient died approximately 21 months after documentation of HIV positivity, with no clinical evidence of systemic lymphoma. Postmortem examination was not performed.
Discussion The occurrence of non-Hodgkin lymphoma associated with AIDS has become well recognized since the first report in 1982.18 In 1985, the presence of a high grade nonHodgkin lymphoma in the setting of HIV positivity was added to the criteria for confirming the diagnosis of AIDS,19 and in 1987 intermediate grade non-Hodgkin lymphoma was added to the diagnostic criteria.2° Extended survival with prolonged immunosuppression and with substantial T4-cell depletion is probably an important factor in the development of these lymphomas. 21 Approximately 20% of patients with AIDS who are affected with non-Hodgkin lymphoma have extranodal involvement, especially in the central nervous system (CNS), compared with less than 1% in patients without AIDS who have non-Hodgkin lymphoma. 22 Non-Hodgkin lymphoma may present with two distinct clinical entities. The first form is primary lymphoma of the CNS (CNSnon-Hodgkin lymphoma), in which tumor may involve the brain parenchyma, meninges, intradural spinal cord, and the posterior segment of the eye. The intraocular lymphoma may be the presenting form of CNS-nonHodgkin lymphoma, antedating CNS or systemic disease by many months.4.23 Intraocular lymphoma associated with CNS-non-Hodgkin lymphoma, formerly referred to as reticulum cell sarcoma, is now referred to as ocular CNS-non-Hodgkin lymphoma. The second form of nonHodgkin lymphoma is systemic lymphoma which may involve the brain by infiltration of the ventricular space or compression of the spinal cord or its nerve roots from locations outside of the dura. Vision may be affected due to invasion of the orbit and only rarely by uveal metastasis. Intraocular lymphoma in immunocompetent patients may result in one of four different clinical forms. The
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most common is the ocular CNS form (reticulum cell sarcoma), producing characteristic multifocal infiltration of the retinal pigment epithelium appearing as solid detachments of the retinal pigment epithelium,24 as well as a PQsterior uveitis. The lymphoma may invade the overlying neurosensory retina and obscure the underlying pigment epithelial detachment, and the retinal whitening may be mistaken for a necrotizing retinitis. With neoplastic infiltration of the inner retina, capillary damage and intraretinal hemorrhage may occur. Thus, there may be areas of necrosis, whitening, and hemorrhage, simulating retinal necrosis as seen in retinitis associated with herpes simplex, herpes zoster, CMV, or toxoplasmosis. 25 Another form of systemic or metastatic non-Hodgkin lymphoma without CNS involvement is associated with lymphomatous infiltration, occurring predominantly in the anterior uveal tract2 6 simulating iridocyclitis,25 or posteriorly resembling fundus flavimaculatusY Other more unusual ocular lymphomatoses include angioendotheliomatosis28 and reactive lymphoid hyperplasia of the uveal tract,29 the latter of which may represent a low-grade B-celllymphoma. 3o Human T-celllymphotropic virus type 1 (HLTV-l) is a known cause of adult T-cell leukemia/lymphoma, and both orbital 31 and intraocular lymphoma have rarely been described in patients infected with HLTV-1. Rao (unpublished data; presented at the Verhoeff Society Meeting, Miami, April 1993) described a patient with HLTV-l who had intraocular lymphoma diagnosed by chorioretinal biopsy. Clinically, the patient was found to have multifocal flat subretinal pale lesions measuring approximately 100 Jim in diameter, increasing in size over time. Histopathologically, lymphomatous infiltration was evident focally within the retina as well as within the subretinal pigment epithelial space. The risk for the development of CNS-non-Hodgkin lymphoma in patients with AIDS has been estimated to be 100 times that of immunocompetent patients. 32,33 In patients with AIDS, the disease has a tendency to be of a
high-grade malignancy with a poor prognosis. Despite the increasing incidence oflymphoma in patients with AIDS, relatively few reports in the literature have documented either intraocular25 ,34,35 or orbital 36-4o lymphoma in this group of patients. Schanzer et al 35 reported a case of a 42-year-old man with HIV who had retinochoroidal lesions in both eyes. The diagnosis of ocular CNS-non-Hodgkin lymphoma was made on a vitrectomy specimen. A spinal fluid cytologic specimen subsequently was positive for lymphoma, and neuroimaging studies showed an asymptomatic lesion in the cerebellum. Gass and Trattler,25 in their report of an immunocompetent patient with ocular lymphoma who had a retinal branch vein occlusion, mentioned a patient with AIDS who had an acute branch retinal arterial occlusion associated with a solid retinal pigment epithelial detachment and retinal infiltration. Magnetic imaging of the brain demonstrated lymphoma which was later confirmed by brain biopsy. The ocular mass was presumed to be lymphoma, which subsequently resolved after radiotherapy. Stanton et al 34 reported an autopsy proven case of primary bilateral intraocular CNS lymphoma in a patient with AIDS. In this case, results of histopathologic examination of the eyes disclosed the bulk of the tumor beneath the retinal pigment epithelium and the subretinal space. In addition, there was lymphomatous infiltration of all layers of the retina. Bruch's membrane was intact, and there was no invasion of the choroid. In addition, no tumor cells were seen in the optic nerve or in the subarachnoid space of the nerve sheath although the brain parenchyma, and the overlying leptomeninges were diffusely involved. Orbital lymphoma is also recognized as a site of extranodal disease, and may present primarily with an orbital mass in 1.0% to 2.4% of cases. 7,8 A few cases of orbital lymphoma have been reported in the context of AIDS. Ziegler et al 18 and Brooks et al40 each reported a case of orbital Burkitt-like lymphoma associated with AIDS. In the case of Brooks et aI, the patient had a 2 lh-year history of a right upper lid swelling. On
) Top left, Figure 1. Fundus photograph of the left eye demonstrates marked disc elevation, peripapillary hemorrhage, and retinitis involving the posterior pole. Top right, Figure 2. Axial computed tomographic scan discloses an irregularly shaped solid mass along the intraorbital course of the left optic nerve. The tumor molds to the posterior aspect of the globe and extends into the left cavernous sinus. Second row left, Figure 3. Biopsy of the left orbit shows large neoplastic lymphocytes with pleomorphic, convoluted nuclei and prominent nucleoli (hematoxylin-eosin; original magnification, X160). Second row right, Figure 4. Massive thickening and necrosis of the retina, retinal pigment epithelium, and choroid. The inner-limiting membrane of the retina (arrowheads) and Bruch's membrane are intact (curved arrow). Scattered, viable neoplastic lymphoma cells are present within the choroid (hematoxylin-eosin; original magnification, XlO). Third row left, Figure 5. Low-power view of the posterior pole demonstrates extensive necrosis of the retina, retinal pigment epithelium, choroid, optic nerve, and nerve sheath (hematoxylin-eosin; original magnification, X5). Bottom right, Figure 6. The scleral canal of the ciliary nerve (asterisk) is surrounded by a lymphomatous infiltrate (L) as well as zones of necrosis (N) (hematoxylin-eosin; original magnification, X12.5). Bottom left, Figure 7. Detachment of necrotic retinal pigment epithelium (arrowheads) overlying a mound of necrotic cells and cellular debris. The underlying choroid is diffusely infiltrated by lymphocytes, plasma cells, and lymphoma cells (hematoxylin-eosin; original magnification, X63).
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CT scan, the mass involved the upper eyelid with posterior extension superiorly and laterally to the apex of the orbit, with inferior displacement of the globe. In an autopsy series, Jabs et al 38 reported one case of orbital lymphoma in a patient with AIDS, without providing any details of the case. Antle et a1 3? reported a case of large cell orbital non-Hodgkin lymphoma associated with AIDS that involved the superomedial orbit. Mansour39 reported a similar case involving the medial orbit that infiltrated the ethmoid sinus. The disease progressed slowly in both of these patients, as is typical of primary orbital lymphoma. Turok and Meyer36 reported a case of non-Hodgkin lymphoma involving the medial orbit that behaved more aggressively than the other reported cases, rapidly displacing, rather than molding to, the globe. Although the conjunctiva, eyelid, lacrimal gland, and orbital muscles are the most frequent periocular tissues involved with orbital lymphoma, the optic nerve may rarely be involved in Hodgkin l2 ,14 or non-Hodgkin lymphoma.9.10.11 ,13 No case of lymphomatous optic neuropathy has been reported in a patient with AIDS. McGavic l5 and Heath l6 reported a combined total of four cases of simultaneous orbital and intraocular lymphoma. Details of these cases, however, are incomplete. Trudeau et al,17 in a review of 87 cases of intraocular lymphoma, report one case of presumed intraocular lymphoma, with simultaneous bilateral optic nerve enlargement on CT. Lymphomatous infiltration of the optic nerves was diagnosed from tissue obtained at the time of Omaya reservoir insertion, but no intraocular specimen was obtained to confirm intraocular lymphoma in this patient. Our patient is unusual, in that he had simultaneous intraocular and orbital lymphoma. Although it is speculative whether the lymphoma occurred primarily within the globe or in the orbit, tumor along the scleral canal of the ciliary nerve suggests contiguous neoplastic spread (Fig 6). Clinically, the patient had retinal findings which might suggest that the non-Hodgkin lymphoma was initially intraocular. The funduscopic findings, namely cystoid macular edema and venous congestion, are an unusual presentation of ocular CNS-non-Hodgkin lymphoma which more typically presents with a posterior vitritis and solid retinal pigment epithelial detachments as described by Gass et al. 24 It is possible that the funduscopic features were secondary to lymphomatous compression at the level of the central retinal vein, due to orbital lymphoma or lymphoma involving the meningeal sheath of the optic nerve. A swollen optic nerve and retinopathy resembling CMV infection subsequently developed; however, this diagnosis was in question when no clinical response to ganciclovir therapy was obtained, The swollen optic nerve and retinopathy could have resulted from lymphomatous infiltration of the optic nerve and retina, or ischemia secondary to neoplastic vascular occlusion, or both. Profound orbital signs developed over the course of weeks, resulting in an orbital apex syndrome. On CT scan,
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the bulk of the tumor was within the orbit, which might suggest that the tumor arose from within the orbit. However, results of histopathologic examination of the enucleated left globe showed malignant cells within intrascleral canals of the ciliary nerves, which suggests that the intraocular and orbital tumors did not arise independently but rather that there was contiguous spread via this interconnecting pathway. Orbital lymphoma typically molds rather than invades tissues, and may cause proptosis by mass effect. A rapidly growing orbital lymphoma has been shown to grossly displace the globe in a patient with AIDS.38 In our patient, the orbital tumor behaved aggressively and displaced the globe anteriorly. Conceivably, the aggressive nature of this tumor might have enabled it to invade the emissary channels, giving rise to secondary intraocular lymphoma. There was no evidence of systemic spread over the course of this patient's 21-month illness, and although no postmortem examination was obtained, we presume that no metastatic disease or extraorbitallymphoma was present. In summary, this patient had simultaneous intraocular and orbital lymphoma with neoplastic spread directly along the scleral canal of the ciliary nerve. Either the orbit or the globe served as the primary site of tumor. While the incidence of lymphoma in patients with AIDS appears to be rising, orbital and intraocular lymphoma is still a rare occurrence, and their co-existence is exceptional. Nevertheless, because lymphoma may masquerade as an intraocular opportunistic infection or orbital inflammatory disease, it behooves all ophthalmologists treating patients with AIDS to be aware of the various clinical presentations of non-Hodgkin lymphoma, and to consider lymphoma in the differential diagnosis of both orbital and intraocular disease, even in the absence of intracranial lymphoma.
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