Journal of Neuro-Ophthalmology, March 2005, Volume 25, Issue 1

The Elusive Nature of Primary Intraocular Lymphoma

A 58-year-old woman with an initial diagnosis of multiple evanescent white dot syndrome OU experienced deteriorating vision despite corticosteroid treatment. Reevaluation disclosed retinal and subretinal infiltrates and pigmentary alterations, prompting a suspicion of primary intraocular lymphoma (PIOL). Diagnostic vitrectomy yielded inconclusive cytology, but flow cytometry demonstrated small monoclonal B cells less suggestive of PIOL than of small lymphocytic lymphoma originating outside the eye or central nervous system. Brain magnetic resonance imaging, chest/abdomen/pelvis computed tomography, lumbar puncture, and laboratory studies failed to disclose lymphoma elsewhere. There was insufficient evidence to recommend radiation therapy. Vision deteriorated rapidly, prompting a diagnostic retinal biopsy and aspiration of the subretinal infiltrate, revealing unequivocal evidence of PIOL. After 40 Gy orbital x-irradiation, visual function improved dramatically. This case emphasizes the unusual ocular manifestations of PIOL and the difficulty of obtaining a definitive diagnosis by sampling vitreous, particularly after corticosteroid treatment. In such cases, subretinal aspiration or retinal biopsy may be necessary. Timely diagnosis is critical because treatment can reverse visual loss if it is not severe.

PHOTO ESSAY The Elusive Nature of Primary Intraocular Lymphoma Daniel K. Fahim, BA, Rodney Bucher, MD, and Mark W. Johnson, MD FIG. 1. Composite fundus photographs at presentation. Diffuse pigmentary alterations and tiny white dots are evident at the level of the retinal pigment epithelium OU. A flat subretinal and intraretinal white infiltrate is seen superotemporally OS. Abstract: A 58- year- old woman with an initial diagnosis of multiple evanescent white dot syndrome OU experienced deteriorating vision despite corticosteroid treatment. Reeval-uation disclosed retinal and subretinal infiltrates and pigmentary alterations, prompting a suspicion of primary intraocular lymphoma ( PIOL). Diagnostic vitrectomy yielded inconclusive cytology, but flow cytometry demonstrated small monoclonal B cells less suggestive of PIOL than of small lymphocytic lymphoma originating outside the eye or central nervous system. Brain magnetic resonance imaging, chest/ abdomen/ pelvis computed tomography, lumbar punc­ture, and laboratory studies failed to disclose lymphoma elsewhere. There was insufficient evidence to recommend radiation therapy. Vision deteriorated rapidly, prompting a diagnostic retinal biopsy and aspiration of the subretinal From the Kellogg Eye Center and Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI. Address correspondence to Mark W. Johnson, MD, University of Michigan Medical School, Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105; E- mail: markwi@ umich. edu infiltrate, revealing unequivocal evidence of PIOL. After 40 Gy orbital x- irradiation, visual function improved dramat­ically. This case emphasizes the unusual ocular manifes­tations of PIOL and the difficulty of obtaining a definitive diagnosis by sampling vitreous, particularly after cortico­steroid treatment. In such cases, subretinal aspiration or retinal biopsy may be necessary. Timely diagnosis is critical because treatment can reverse visual loss if it is not severe. ( J Neuro- Ophthalmol 2005; 25: 33- 36) A58- year- old woman had floaters in both eyes attributed to the multiple evanescent white dot syndrome. De­spite prednisone therapy, her vision continued to deterio­rate. Extensive laboratory studies, chest x- ray, and brain magnetic resonance imaging were negative. She had a long history of rheumatoid arthritis treated with prednisone 20 mg/ d, infliximab, methotrexate, and rofecoxib. Because of a positive purified protein derivative patch test, she had also received oral anti- tuberculous therapy. Our examination disclosed visual acuities of 20/ 25 OD and 20/ 50 OS. There were cells in the anterior chamber J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 33 J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 Fahim et al OU. Ophthalmoscopy OD showed cells in the posterior vitreous and scattered yellow- brown pigment clumps and tiny white dots at the level of the retinal pigment epi­thelium. Ophthalmoscopy OS disclosed moderate vitreous debris, coarse pigment clumps, small white lesions at the retinal pigment epithelium level, areas of retinal pigment ep­ithelium atrophy, and a large, flat, white retinal and sub-retinal infiltrate above the superotemporal arcade ( Fig. 1). Fluorescein angiography showed extensive pigmen­tary alterations in both eyes in a leopard- spot pattern ( Fig. 2). There was relative blocking of background fluo­rescence by the white infiltrate superiorly in the OS. There was no vascular occlusion or significant vascular leakage in this area. After diagnostic vitrectomy OS, cytologic analysis showed mixed inflammatory cells and several atypical small cells without definite evidence for lymphoma. Flow cytometry showed that the vitreous lymphocytes were ap­proximately 85% of B- cell origin and were monoclonal with kappa light chain restriction. Together with the small cell morphology found on cytologic examination, the flow cytometric results suggested a diagnosis of systemic B- cell small lymphocytic lymphoma rather than a primary in­traocular lymphoma ( PIOL). However, lumbar puncture, brain and orbital magnetic resonance imagings, chest/ ab­domen/ pelvis computed tomography scans, complete blood count with differential, and flow cytometry of peripheral blood showed no evidence of lymphoma elsewhere. Oncologists were reluctant to recommend radiation therapy without a definite cytologic diagnosis. Visual acuity declined over a 3- week period to 20/ 300 OD, finger counting OS. Repeat ophthalmoscopy showed progression of the previous findings ( Fig. 3). Subretinal fine needle aspiration and retinal biopsy revealed unequivocal large B- cell lymphoma characteristic of PIOL. The patient re­ceived bilateral 40 Gy orbital radiation therapy in 20 fractions. One month after radiation therapy, visual acuity measured 20/ 20 OD and 20/ 60 OS. Fundus examination revealed marked resolution of lymphomatous infiltrates ( Fig 4). Although intraocular lymphoma is frequently asso­ciated with primary central nervous system lymphoma, no extraocular manifestations are initially present in 14% to 22% of patients ( 1,2). PIOL is a rare malignancy, but its incidence has increased dramatically in part because of the expanding immunodeficient patient population ( 3). The diagnosis of PIOL requires a high index of suspicion because it may present with numerous clinical variations ( 4- 6). Even after the disease is suspected, it may be difficult to confirm with commonly used diagnostic modalities. Cy-tological examination of vitreous specimens is often inconclusive ( 7- 11). This is caused in part by the paucity and friability of malignant lymphoid cells in the vitreous ( 5,10,11). The desire for higher diagnostic yield has led to the increased use of manual or automated immunohisto-chemical techniques such as flow cytometry, polymorphism analysis, or polymerase chain reactions ( 8- 11). In our patient's case, vitreous cytology was inconclusive, whereas flow cytometry supported the correct diagnosis. A confounding factor in our case was chronic corticosteroid administration for rheumatoid arthritis and FIG. 2. Fluorescein angiography at presentation. It shows extensive retinal pigmentary alteration in a leopard- spot pattern OU. 34 2005 Lippincott Williams & Wilkins Elusive Nature of Primary Intraocular Lymphoma J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 FIG. 3. Composite fundus photographs 3 weeks after presentation, before initiation of ocular x- irradiation. They show worsening of the findings noted in Figure 1. a recent boost in dose when uveitis was diagnosed. This is a common problem, because the diagnosis of intraocular lymphoma is often considered only after a patient has been resistant to corticosteroid treatment of presumed uveitis ( 4,5). Previous authors have suggested that prednisone administration before vitreous biopsy may result in a lower diagnostic yield by causing lysis of malignant cells ( 10). Given the imperfect sensitivity of vitreous biopsy in PIOL, several researchers have resorted to chorioretinal biopsy ( 5,7,12,13). In our patient, the diagnosis was not confirmed until retinal and subretinal specimens were obtained. In patients with subretinal infiltrates, performing a subretinal aspiration in conjunction with diagnostic vitrectomy may be diagnostically sufficient and retinal biopsy, a more hazardous procedure, can usually be avoided ( 5,12). The treatment of PIOL without detectable central nervous system involvement remains controversial. Our FIG. 4. Composite fundus photographs one month after completion of ocular x- irradiation ( 40 Gy). They show a marked lessening of the previously noted abnormalities. 35 J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 Fahim et al patient had complete regression of lymphomatous infil­trates and dramatic visual improvement with orbital ra­diotherapy alone. Intravitreal methotrexate has been used successfully for the initial treatment of PIOL, but more commonly for recurrent disease, often in combination with other locally administered agents such as thiotepa or dexamethasone ( 14- 18). Prophylactic whole- brain irradi­ation, systemic chemotherapy, and intrathecal chemother­apy are rational treatment modalities given the high incidence of subsequent central nervous system involve­ment ( 4). However, these therapies may be associated with significant morbidity, especially in elderly patients. Our case emphasizes the variegated appearance of PIOL and the importance of having a high index of sus­picion for this diagnosis even when ophthalmoscopic findings are not altogether typical. We also underscore the fact that tissue diagnosis may be difficult, particularly when corticosteroid treatment has been given. Cytology and even flow cytometry of vitreous specimens may be inconclusive, necessitating subretinal aspiration or even retinal biopsy. Timely diagnosis is imperative considering that treatment of PIOL may be effective in restoring vision if damage is not severe. REFERENCES 1. Hoffman PM, McKelvie P, Hall AJ, et al. Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye. 2003; 17: 513- 21. 2. Freeman LN, Schachat AP, Knox DL, et al. Clinical features, laboratory investigations and survival in ocular reticulum cell sarcoma. Ophthalmology. 1987; 94: 1631- 1639. 3. Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin Ophthalmol. 2002; 13: 411- 8. 4. Gill MK, Jampol LM. Variations in the presentation of primary intra­ocular lymphoma: case reports and a review. Surv Ophthalmol. 2001; 45: 463- 71. 5. Levy- Clarke GA, Byrnes GA, Buggage RR, et al. Primary intraocular lymphoma diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina. 2001; 21: 281^ k 6. Velez G, Chan CC, Csaky KG. Fluorescein angiographic findings in primary intraocular lymphoma. Retina. 2002; 22: 37^ 3. 7. Coupland SE, Bechrakis NE, Anastassiou G, et al. Evaluation of vitrectomy specimens and chorioretinal biopsies in the diagnosis of primary intraocular lymphoma in patients with masquerade syndrome. Graefes Arch Clin Exper Ophthalmol. 2003; 241: 860- 70. 8. Davis JL. Diagnosis of intraocular lymphoma. Ocular Immunol Inflam­mation. 2004; 12: 7- 16. 9. Gorochov G, Parizot C, Bodaghi B, et al. Characterization of vitreous B- cell infiltrates in patients with primary ocular lymphoma, using CDR3 size polymorphism analysis of antibody transcripts. Invest Ophthalmol Visual Sci. 2003; 44: 5235^ 1. 10. Whitcup SM, Chan CC, Buggage RR, et al. Improving the diagnostic yield of vitrectomy for intraocular lymphoma. Arch Ophthalmol. 2000; 118: 446. 11. Zaldivar RA, Martin DF, Holden JT, et al. Primary intraocular lymphoma: Clinical, cytologic, and flow cytometric analysis. Ophthal­mology. 2004; 111: 1762- 1767. 12. Ciulla TA, Pesavento RD, Hoo S. Subretinal aspiration biopsy of ocular lymphoma. Am J Ophthalmol. 1997; 123: 420- 2. 13. Coupland SE, Heimann H. Primary intraocular lymphoma. Oph­thalmology 2004; 101: 87- 98. 14. Batchelor TT, Kolak G, Ciordia R, et al. High- dose methotrexate for intraocular lymphoma. Clin Cancer Res. 2003; 9: 711- 5. 15. de Smet MD, Vanes VS, Kohler D, et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol. 1999; 83: 448- 51. 16. Helbig H, Cerny T, de Smet MD. Intravitreal chemotherapy for intraocular lymphoma. Ophthalmologe. 2003; 100: 145- 9. 17. Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology. 2002; 109: 1709- 16. 18. Velez G, Boldt HC, Whitcup SM, et al. Local methotrexate and dexamethasone phosphate for the treatment of recurrent primary intraocular lymphoma. Ophthal Surg lasers. 2002; 33: 329- 33. 36 © 2005 Lippincott Williams & Wilkins