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Primary Intraocular Lymphoma (ocular reticulum cell sarcoma) Diagnosis and Management
Primary Intraocular Lymphoma (ocular reticulum cell sarcoma) Diagnosis and Management DEVRON H. CHAR, MD,t BRUT-MARIE LJUNG, MD,2 THEODORE MILLER, MD, 2 THEODORE PHILLIPS, MIY
Abstract: The authors retrospectively reviewed the diagnosis and manage ment of 20 intraocular lymphoma patients who initially presented with either ocular or central nervous system (CNS) disease. As the ophthalmic community has become more aware of this entity, the interval between symptoms and diagnosis has significantly shortened. Diagnosis can usually be made on cyto pathologic examination of vitreous cells. However, in three cases more than one vitreous biopsy was necessary. Results of cytologic examination appeared to be more accurate than those of conventional lymphocyte surface marker stud ies in the diagnosis of an intraocular lymphoma. Long-term survival occurred in some patients treated with a combination of intrathecal chemotherapy and ocular/CNS irradiation. [Key words: cytology, intraocular lymphoma, ocular radi ation, reticulum cell sarcoma.] Ophthalmology 95:625-630, 1988
Primary intraocular lymphoma can occur as an iso lated eye tumor or involve both the globe and the central nervous system (CNS). 1 Secondary lymphoma also may involve the eye as a result of a systemic tumor. The syndrome was first recognized in 1951; approximately 80 cases have been reported. 2- 10 The initial term used to describe it, ocular reticulum cell sarcoma, is a mis nomer. Investigators thought the tumor consisted of malignant reticulum cells. Recent data demonstrate that these tumors are predominantly large cell lymphomas
Originally received: November 9, 1987. Revision accepted: January 22, 1988. 1 2
3
Ocular Oncology Unit, Department of Ophthalmology, and the Francis I. Proctor Foundation, University of California, San Francisco. Department of Pathology, University of California, San Francisco. Department of Radiation Oncology, University of California, San Fran cisco.
Supported in part by an unrestricted grant from That Man May See, the Beal Foundation, Richard and Gail Siegal Foundation, and by NIH grant EY03675, and American Cancer Society grant PDT 321. Reprint requests to Devron H. Char, MD, Ocular Oncology Unit, Science 315, Box 0412, University of California, San Francisco, CA 94143.
and consist of either malignant lymphocytes or their precursors. 11 - 14 Most commonly, this malignancy occurs in older patients; however, patients as young as 28 years of age have been described. 15 Usually patients are initially misdiagnosed as having a chronic diffuse uveitis or vitritis that is nonresponsive to steroids. Even tually, CNS lymphoma develops in most patients and they die from it. 3 There are a number of unresolved issues regarding this tumor; we addressed three questions in this retro spective study. First, the diagnostic sensitivity of vitre ous biopsies is uncertain. 7 •8• 15·16 Similarly, the value of immunodiagnostic studies on vitreous cells remains un clear. Tumor monoclonality has been noted; however, some cases were associated with systemic lymphoid ma lignancies. In other vitreous specimens, admixtures of inflammatory, polyclonal, or null cells have been found. 15-20 Second, in some series, patients with primary intraocular lymphoma with or without CNS disease, have been admixed with patients with ocular involve ment secondary to a systemic lymphoid malig nancy.3·21-23 Probably these are two different disease processes with different prognoses. Third, it is uncertain what the most effective therapies for intraocular lym 625
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phoma are. 3•24- 26 We have reviewed 20 intraocular lym phoma patients examined and managed at our institu tion to attempt to delineate accuracy of vitreous studies and the effect oftreatment on this disease. Some ofthese cases have been reported previously. 3•15•21
MATERIALS AND METHODS Twenty patients were referred to the University of California, San Francisco; 13 were evaluated by one of us (DHC), and the diagnosis of an intraocular lym phoma was made on the basis of histologic or cytologic criteria in all cases. Initial patients studied between 1968 and 1975 did not have computed tomographic (CT) evaluations, the remainder did. All patients had a com plete physical examination, bone marrow biopsies, complete blood counts, and cerebrospinal fluid (CSF) cytology. In 14 cases, vitreous biopsies were performed. Both body and brain CT examinations with contrast were done on all patients examined after 1976. In seven patients studied before 1974, vitreous sam ples were obtained through the pars plana using a needle and syringe. In the remaining 13 patients, the choice ofa needle aspirate versus vitrectomy was predicated on the opacity of the vitreous. Four patients with minimal vit reous involvement and good vision (>20/60) had a pars plana aspirate with a 20-gauge needle to obtain a vitre ous specimen. In two of these four cases, core vitrecto mies were performed later because of vitreous clouding. In nine patients with more extensive vitreous involve ment, a core vitrectomy was performed. In these pa tients, an infusion port was sutured in place, and an MVR blade was used to make incisions for a light pipe and a vitrectomy instrument. Before placing the vitrec tomy instrument in the eye, approximately 1 ml of liq uid vitreous was aspirated with a 20-gauge blunt needle. No complications were noted as a result of aspiration. Cytologic specimens were handled in a standard manner. 27 •28 All CSF and vitreous specimens were pro cessed through a negative pressure, 5-~-tm millipore filter, and fixed overnight in 95% ethanol. They were stained with a modified Papanicolaou technique. Cytologic features analyzed included overall cellular ity, cell size, presence of necrotic debris, polymorphonu clear leukocytes, mitotic figures, nucleoli, the degree of nuclear membrane and chromatin irregularity, and the proportion of abnormal cells. In nine cases studied between 1980 and 1986, vitreous needle biopsies were divided in two parts and taken from the operating room to the laboratory for immedi ate cytologic and immunologic analysis. In three cases, a separate, second sample was simultaneously analyzed; this was obtained through the vitrectomy instrument and harvested from the balanced salt solution plus-spec imen reservoir. Immunologic evaluation of vitreous cells was per formed in three early cases using rosette techniques, and in six cases with a fluorescence-activated cell sorter 626
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(FACS IV, Becton Dickinson Co, Sunnyvale, CA) using dual-channel, two-color techniques. 29 - 31 Fluorescein isothyocyanate or phycoerythrin-conjugated mono clonal antibodies (a gift from Becton-Dickinson) were used including Leu 2a (T cytotoxic/suppressor cells), Leu 3a (T helper/inducer cells), Leu 4 (total T-cells), Leu 16 (total B-cells), Leu 11 (T suppressor cells, large granular lymphocytes, and natural killer cells), and IL-2 (activated T -cells). Treatment protocols have been modified over time, and not all patients received radiation therapy at the same institution. Generally, patients with combined eye and CNS disease were treated with a combination of intrathecal methotrexate and photon irradiation to the CNS and spinal cord.3•21
RESULTS Nineteen of 20 cases were diagnosed at our institu tion. The mean age of patients was 61 years (range, 35-82 years). Ocular symptoms, most commonly either floating spots or decreased vision, were the presenting sign of the disease in 13 cases. Seven of 20 patients initially presented with CNS symptoms before the dis covery of ocular disease; four had the diagnosis of a cerebral lymphoma confirmed before the diagnosis of the eye tumor. Eventually, 16 of 20 had evidence of CNS involvement. The interval between first ocular or nervous system symptoms and diagnosis was 0 to 60 months. There was a significant difference in the inter val between symptoms and diagnosis in the 11 patients examined before 1980 as compared with the 9 patients evaluated after that date; the mean interval in the first group was 24.3 months versus 5.8 months in the latter group (Student's t test; P < 0.006). No patient presented with systemic lymphoma; systemic malignancy devel oped in three patients between 18 and 36 months after the ocular diagnosis was established. In two of three patients, there was ocular, CNS, and systemic lym phoma. One patient had only ocular and systemic in volvement. Ocular involvement was bilateral in 18 of 20 cases; all patients had vitreous cells and in 15 there was evidence ofcellular anterior segment involvement (Table 1). Reti nal lesions were noted in 16 cases. In most patients, there was marked asymmetry in both cellularity and retinal lesions. Irregular, poorly defined, yellowish, or white retinal or chorioretinal lesions were typical as shown in Figure 1. Often it was not possible on the basis of clinical examination to determine whether these tumors were confined to a specific retinal, retinal pig ment epithelial, or choroidal layer. In two cases, a signif icant hemorrhagic retinal component was noted, and one patient had an exudative detachment. Four patients had no obvious retinal lesions; one had eye and CNS disease and died, two had only eye involvement and are alive, and one is alive after treatment for ocular and CNS lymphoma.
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Table 1. Clinical Parameters in 22 Patients with Primary Intraocular Lymphoma Parameters Vitreous cells Anterior segment cells Retinal, RPE, and choroidal lesions Bilateral eye disease Central nervous system involvement Mean age (yrs)
No. of Patients 20
15 16 18 16 61
RPE = retinal pigment epithelial.
Brain CT with contrast, using second- through fourth-generation scanners, demonstrated brain lesions in five cases; two patients had magnetic resonance image scans that mirrored the pathology noted on CT brain scan. In all lesions that were diagnosed on either CT or magnetic resonance imaging, a discrete tumor mass was noted. Results of CSF cytologic examination were posi tive in six cases. In one CT-positive case, results of the CSF cytologic examination were negative, and one pa tient with positive results of cytologic examination had a negative CT scan. Four cytologic features were characteristic for the diagnosis of intraocular lymphoma: irregular nuclear contours, lobation of nuclei, coarse irregular chromatin, and presence of nucleoli (Fig 2). Mitoses were occasion ally observed in intraocular lymphoma specimens, and necrotic material was sometimes present. Inflammatory cells were infrequent. In three patients with symmetrical disease, the diag nosis could not be made either prospectively or retro spectively on the initial vitreous biopsy. In one of these patients, the first eye had two separate biopsies (anini tial diagnostic procedure followed several months later by a therapeutic vitrectomy) with only inflammatory cells noted on both cytologic and immunologic evalua tions. A third vitreous biopsy at a later time established the diagnosis; retrospective analysis of the two earlier specimens was negative for malignancy. In the second patient, because of strong clinical suspicion and an equivocal CSF cytologic examination, the contralateral vitreous was removed l week later and a cytologic diag nosis of intraocular lymphoma was established. The third patient had been treated with radiation at another institution without a diagnosis, then referred with recur rent visual symptoms 2 years later. At that time, a sec ond vitreous biopsy was positive. In three cases, we compared vitreous cytologic detail from specimens removed directly from the eye with a 20-gauge needle versus material taken through the vi trectomy unit and obtained from the aspiration reser voir. Figures 3 and 4 demonstrate the loss of cellular detail that occurred when the specimen was obtained through vitrectomy instrumentation. The relative con tribution of the vitrectomy instrument versus maintain ing the cells for 30 to 60 minutes in a balanced salt plus reservoir is unclear.
Fig 1. Clinical photograph of intraocular lymphoma with typical cho rioretinal infiltrates.
Fig 2. Vitreous sample from patient showing typical lobation of nuclei, and coarse irregular chromatin.
Immunologic assessment of cell type was performed on multiple specimens from the nine cases studied. 15 Six specimens were not typeable with the reagents used, and defined as null cell lymphomas. Two specimens were polyclonal, and two consisted of probable T-cell neo plasms. In contrast to patients with benign forms of uveitis that usually have significant numbers of acti vated (IL-2 positive) intraocular T -cells, less than 1% of 627
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20 months (range, 1-31 months). The mean survival in living patients treated since 1978 is 41 months (range, 18-109 months); two of these patients have been fol lowed for less than 2 years after therapy.
DISCUSSION
Fig 3. Vitreous cells obtained from a 20-gauge needle.
Fig 4. Vitreous specimen from same case as Figure 3 obtained through a vitrectomy instrument. Both samples were processed in an identical manner simultaneously.
cells in the six diagnostic intraocular lymphoma speci mens studied were positiveY Follow-up and treatment data are summarized in Table 2. The radiation and chemotherapy protocols used with these patients have been described pre viously.3 Recent patients with eye and CNS disease have received 45 Gy of photon radiation to the eyes and whole-brain plus intrathecal methotrexate. Three of 11 patients treated before 1977 are alive. Systemic recur rences developed in two patients 7 and 4 years after initial diagnosis; after systemic chemotherapy, they re main in good health 3 and 4 years later. The interval between diagnosis and death in patients who died ofthis disease ranged from 5 to 39 months (mean, 15.8 months). Three of nine patients treated since 1978 have died; the mean interval between diagnosis and death was 628
Intraocular lymphoma, that is not a sequelae of a malignant systemic lymphoid tumor, is an unusual neo plasm with a predilection for the eye and CNS. Central nervous system tumor usually develops in most patients with this intraocular lymphoma; in the current study, this occurred in 16 of 20 patients (80%). This incidence of CNS lymphoma is slightly higher than noted in some reviews; however, the follow-up of our patients was complete, and the observation that late CNS disease de velops in some patients probably accounts for this dif ference.7·9 Similar to previous studies, we noted that most patients initially presented with ocular involve ment, and both vitreous cells and typical yellowish white retinal infiltrates were common. Although some investigators have stated that the involvement of uvea versus retina is more common when the lymphoma is associated with systemic versus CNS disease, this was not our uniform experience. 22·26 In four patients, there was no evidence ofa retinal or choroidal mass, and three other patients had somewhat atypical findings including an exudative detachment, hemorrhagic retinal changes, or neovascular glaucoma; others have noted similar findings. 10• 19·22·32 Often it is not possible to clinically de lineate a lesion as arising from a single layer (i.e., cho roid, retinal pigment epithelium, or retina). Vitreous biopsy could establish the diagnosis of intra ocular lymphomas in over 95% of patients. In a small study where we compared the sensitivity of cytologic with lymphocyte subset analysis, we noted that the former technique was more accurate. 15 We observed lymphocyte heterogeneity on immunologic analysis of lymphocyte surface markers in at least six of nine pa tients studied. 15 This finding limits the use of lympho cyte marker analysis as a method of diagnosing intra ocular lymphoma. The apparent lack of tumor mono clonality could be due to many causes. It is possible that a normal population of inflammatory cells is admixed with the tumor population to produce the heterogeneity observed. 33 ·34 In previous studies of intraocular lym phomas, an admixture of benign inflammatory cells has been noted. 5·17·35 ·36 Biclonal or triclonal populations of lymphoma cells can occur. 36 Newer Southern blot anal ysis can detect a much smaller percentage monoclonal population than is possible with the techniques we used; however, it is still quite difficult to do those studies on fine-needle aspiration biopsies, and it is costly. 33 ·37 ·38 The accuracy of a negative vitreous aspirate is uncer tain. In some cases, a single vitreous biopsy was not always adequate to establish a diagnosis. We have exam ined specimens from other institutions in which a false negative cytologic diagnosis occurred (unpublished data). In some of these cases, specimens were poorly
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prepared, whereas in others an inaccurate interpretation led to an incorrect diagnosis. In our experience, there was cellular degradation in three cases when specimens were obtained with vitrectomy instrumentation as com pared with samples from a needle and syringe. It is un certain whether loss ofcellular detail was from the irriga tion solution or the mechanical action of the vitreous cutter, but optimization ofcell preservation is important to establish the correct diagnosis. All of our cases had liquid vitreous secondary to both tumor and inflamma tion, and no apparent damage occurred from a fine-nee dle aspiration biopsy. In some cases, probably either a random sampling error or a relative lack of tumor cells at the time of vitreous biopsy resulted in a false-negative diagnosis. 38 In this series, three patients required more than one vitreous biopsy to establish the diagnosis. Vit reous biopsy and analysis of the vitrectomy fluid from the clinically more involved eye was not always diag nostic. Many reports have stressed the dismal prognosis of patients with intraocular lymphoma. In our initial radia tion study, eight of nine patients eventually died of their disease. 21 In a review of 68 patients, 45 (69%) died. 9 In 1981, we reported on long-term survival in three pa tients treated with a combination of radiation to the eyes and CNS plus adjunctive intrathecal chemotherapy. 3 Others have noted that these intraocular lymphomas are often sensitive to chemotherapy. 8•24•25 Our data demon strate improved survival when patients with intraocular and CNS lymphoma are treated with a combination of intrathecal chemotherapy and both eye and whole-brain irradiation to 40 to 45 rad in 25 to 30 fractions. Seven of nine patients treated since 1978 are alive. The optimum management of these cases with com bined eye and CNS disease is uncertain. We have dem onstrated that many such patients can be salvaged with a combination ofbrain-ocular irradiation plus intrathecal chemotherapy. In general, patients with gross CNS dis ease that is symptomatic do poorly, whereas asympto matic patients with either only small foci of CNS lym phoma demonstrable with CT/magnetic resonance imaging, positive CSF cytologies, or no CNS disease ap pear to respond much better to treatment. Unfortu nately, almost 10% of such patients have experienced obvious CNS morbidity after aggressive therapy, and recurrent disease has developed in two patients outside ofthe eye or CNS several years later. In both ofthe latter cases, systemic chemotherapy appears to have produced long-term survivals without further recurrences. The management of patients with only ocular in volvement remains an enigma. One such patient re ported by Hogan and Klingele26 had only enucleation and died of other causes; however, there was tumor present in other sites at postmortem examination. Other authors have anecedotal reports of patients cured with only enucleation. 4 •25 In this series, two patients with iso lated ocular involvement had only ocular radiation with no recurrent disease 24 and 109 months after treatment. More follow-up is necessary, since the interval between the diagnosis of ocular lymphoma and development of
Table 2. Therapies and Their Effect*
Therapy Ocular and CNS radiation Ocular radiation alone Eye/CNS radiation plus chemotherapy* Systemic chemotherapy alone Enucleation alone
Alive (mean survival, mos) 0 2 (24, 109) 8 (122, 140, 96, 18, 48, 18, 29, 30)
Died of Tumor (mean survival, mos) 4 (1, 24, 9, 39) 0 4 (5, 21, 7, 31) 1 (12)
10
1 (9)
CNS = central nervous system. * All surviving patients in this group received radiation to the eye and brain plus intrathecal chemotherapy; three patients in deceased group received simi liar chemotherapy. Some patients received systemic chemo therapy for extra-CNS disease.
CNS disease can have a latency of as long as 10 years. 39•40 It is apparent that even with modern diagnos tic modalities, it is difficult to correctly diagnose this malignancy; however, our series shows that as the oph thalmic community has recognized this tumor, the in terval between symptom onset and correct diagnosis has significantly diminished. Since some of these patients can be effectively treated, it is of paramount importance to make an early diagnosis.
REFERENCES 1. Char DH. Clinical Ocular Oncology. New York: Churchill Livingstone, 1988 (in press). 2. Cooper EL, Riker JL. Malignant lymphoma of the uveal tract. Am J Ophthalmol1951; 34:1153-8. 3. Char DH, Margolis L, Newman AB. Ocular reticulum cell sarcoma. Am J Ophthalmol1981; 91:480-3. 4. Vogel MH, Font RL, Zimmerman LE, Levine RA. Reticulum cell sar coma of the retina and uvea: report of six cases and review of the literature. Am J Ophthalmol1968; 66:205-15. 5. Nevins RC Jr, Frey WW, Elliott JH. Primary, solitary, intraocular reticu lum cell sarcoma (microgliomatosis): (a clinicopathologic case re port). Trans Am Acad Ophthal Otolaryng 1968; 72:867-76. 6. Rosenbaum TJ, MacCarty CS, Buettner H. Uveitis and cerebral retic ulum-cell sarcoma (large cell lymphoma): case report. J Neurosurg 1979; 50:660-4. 7. Rockwood EJ, Zakov ZN, Bay JW. Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma): report of three cases. J Neurosurg 1984; 61:369-74. 8. Caya JG, Clowry LJ, Wollenberg NJ, et al. The clinicopathologic significance of vitreous fluid cytology examinations in a series of 38 patients. Diag Cytopathol 1985; 1:267-71. 9. Corriveau C, Easterbrook M, Payne D. Lymphoma simulating uveitis (Masquerade Syndrome). Can J Ophthalmol1986; 21:144-9. 10. Sloas HA, Starling J, Harper DG, Cupples HP. Update of ocular reticulum cell sarcoma. Arch Ophthalmol1981; 99:1048-52, 11. Rappaport H. Tumors of the Hematopoietic System. Washington, DC: Armed Forces Institute of Pathology, 1966.
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12. Taylor CR. Russell R, Lukes RJ, Davis RL. An immunohistological study of immunoglobulin content of primary central nervous system lymphomas. Cancer 1978; 41 :2197-205. 13. Varadachari C, Palutke M, Climie ARW, et al.lmmunoblastic sarcoma (histiocytic lymphoma) of the brain with B cell markers. J Neurosurg 1978; 49:887-92. 14. Warnke R, Miller R, Grogan T, et al. Immunologic phenotype of 30 patients with diffuse large-cell lymphoma. N Engl J Med 1980; 303:293-300. 15. Char DH, Ljung B-M, Deschenes J, Miller TR. Intraocular lymphoma: immunologic and cytologic analysis. Br J Ophthalmol (in press). 16. Michels RG , Knox DL, Erozan YS , Green WR . Intraocular reticulum cell sarcoma: diagnosis by pars plana vitrectomy. Arch Ophthalmol 1975; 93:1331-5. 17. Kennerdell JS, Johnson BL, Wisotzkey HM. Vitreous cellular reaction: association with reticulum cell sarcoma of brain. Arch Ophthalmol 1975; 93:1341-5. 18. Kaplan HJ, Meredith TA, Aaberg TM, Keller RH. Reclassification of intraocular reticulum cell sarcoma (histiocytic lymphoma): immuno logic characterization of vitreous cells. Arch Ophthalmol 1980; 98:707-10. 19. Michelson JB, Michelson PE, Bardin GM, Chisari FV. Ocular reticulum cell sarcoma: presentation as retinal detachment with demonstration of monoclonal immunoglobulin light chains of the vitreous cells. Arch Ophthalmol 1981; 99:1409-11 . 20. Deschenes J, Freeman WR, Char DH, Garovoy MR. Lymphocyte subpopulations in uveitis. Arch Ophthalmol1986; 104:233-6. 21. Margolis L, Fraser R, Lichter A, Char DH. The role of radiation therapy in the management of ocular reticulum cell sarcoma. Cancer 1980; 45:688-92. 22. Kim EW, Zakov ZN, Albert DM, et al. Intraocular reticulum cell sar coma: a case report and literature review. Albrecht von Graefes Arch Klin Exp Ophthalmol 1979; 209:167-78. 23. Givner I. Malignant lymphoma with ocular involvement: a clinico pathologic report. Am J Ophthalmol 1955; 39:29-32. 24. Baumann MA, Ritch PS, Hande KR , et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986; 57:1273-5. 25. Sullivan SF, Dallow RL. Intraocular reticulum cell sarcoma: its dra matic response to systemic chemotherapy and its angiogenic poten tial. Ann Ophthalmol 1977; 9:401-6.
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26. Klingele TG, Hogan MJ. Ocular reticulum cell sarcoma. Am J Oph thalmol1975; 79:39-47. 27. Del Vecchio PR, DeWitt SH, Borelli Jl, et al. Application of rnillipore filtration technique to cytologic material. J Natl Cancer lnst 1959; 22:427-31. 28. Reynaud AJ, King EB. A new filter for diagnostic cytology. Acta Cytol 1967; 11:289-94. 29. Freeman WR, Char DH, Garavoy MR, Lyon H. Microtechniques for flow cytometric analysis of aqueous humor lymphocytes. J lmmunol Methods 1984; 73:447-55. 30. Char DH. Immunology of Uveitis and Ocular Tumors. New York: Grune & Stratton, 1978. 31 . Deschenes J, Char DH, Kaleta S. Activated T lymphocytes in uveitis. Br J Ophthalmol 1988; 72 (in press). 32. Gass JDM, Sever RJ, Grizzard WS, et al. Multifocal pigment epithelial detachments by reticulum cell sarcoma: a characteristic funduscopic picture. Retina 1984; 4:135-43. 33. Stein RS, Cousar J, Flexner JM, Collins RD. Correlations between immunologic markers and histopathologic classifications: clinical im plications. Semin Oncol1980; 7:244-54. 34. Arnold A, Cossman J, Bakhshi A. et al. Immunoglobulin-gene rear rangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med 1983; 309:1593-9. 35. Qualman SJ, Mendelsohn G, Mann RB, Green WR. Intraocular lym phomas: natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer 1983; 52:878-86. 36. Wilke G. Ober primare Reticuloendotheliosen des Gehirns mit be sonderer BerOcksichtigung bisher unbekannter eigenartiger granulo matoser Hirnprozesse. Disch Z Nervenheilkd 1950; 164:332-80. 37. Siegelman MH, Cleary JL, Warnke R, Sklar J. Frequent biclonality and lg gene alterations among B cell lymphomas that show multiple histo logic forms. J Exp Med 1985; 161:850-63. 38. Bertness V, Kirsch I, Hollis G. et al. T-cell receptor gene rearrange ments as clinical markers of human T-celllymphomas. N Engl J Med 1985; 313:534-8. 39. Lang GK, Surer JL, Green WR, et al. Ocular reticulum cell sarcoma: clinicopathologic correlation of a case with multifocal lesions. Retina 1985; 5:79-86. 40. Barr CC, Green WR, Payne JW, et al. Intraocular reticulum cell sar coma: clinicopathologic study of four cases and review of the litera ture. Surv Ophthalmol1975; 19:224-39.
Abstract: The authors retrospectively reviewed the diagnosis and manage ment of 20 intraocular lymphoma patients who initially presented with either ocular or central nervous system (CNS) disease. As the ophthalmic community has become more aware of this entity, the interval between symptoms and diagnosis has significantly shortened. Diagnosis can usually be made on cyto pathologic examination of vitreous cells. However, in three cases more than one vitreous biopsy was necessary. Results of cytologic examination appeared to be more accurate than those of conventional lymphocyte surface marker stud ies in the diagnosis of an intraocular lymphoma. Long-term survival occurred in some patients treated with a combination of intrathecal chemotherapy and ocular/CNS irradiation. [Key words: cytology, intraocular lymphoma, ocular radi ation, reticulum cell sarcoma.] Ophthalmology 95:625-630, 1988
Primary intraocular lymphoma can occur as an iso lated eye tumor or involve both the globe and the central nervous system (CNS). 1 Secondary lymphoma also may involve the eye as a result of a systemic tumor. The syndrome was first recognized in 1951; approximately 80 cases have been reported. 2- 10 The initial term used to describe it, ocular reticulum cell sarcoma, is a mis nomer. Investigators thought the tumor consisted of malignant reticulum cells. Recent data demonstrate that these tumors are predominantly large cell lymphomas
Originally received: November 9, 1987. Revision accepted: January 22, 1988. 1 2
3
Ocular Oncology Unit, Department of Ophthalmology, and the Francis I. Proctor Foundation, University of California, San Francisco. Department of Pathology, University of California, San Francisco. Department of Radiation Oncology, University of California, San Fran cisco.
Supported in part by an unrestricted grant from That Man May See, the Beal Foundation, Richard and Gail Siegal Foundation, and by NIH grant EY03675, and American Cancer Society grant PDT 321. Reprint requests to Devron H. Char, MD, Ocular Oncology Unit, Science 315, Box 0412, University of California, San Francisco, CA 94143.
and consist of either malignant lymphocytes or their precursors. 11 - 14 Most commonly, this malignancy occurs in older patients; however, patients as young as 28 years of age have been described. 15 Usually patients are initially misdiagnosed as having a chronic diffuse uveitis or vitritis that is nonresponsive to steroids. Even tually, CNS lymphoma develops in most patients and they die from it. 3 There are a number of unresolved issues regarding this tumor; we addressed three questions in this retro spective study. First, the diagnostic sensitivity of vitre ous biopsies is uncertain. 7 •8• 15·16 Similarly, the value of immunodiagnostic studies on vitreous cells remains un clear. Tumor monoclonality has been noted; however, some cases were associated with systemic lymphoid ma lignancies. In other vitreous specimens, admixtures of inflammatory, polyclonal, or null cells have been found. 15-20 Second, in some series, patients with primary intraocular lymphoma with or without CNS disease, have been admixed with patients with ocular involve ment secondary to a systemic lymphoid malig nancy.3·21-23 Probably these are two different disease processes with different prognoses. Third, it is uncertain what the most effective therapies for intraocular lym 625
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phoma are. 3•24- 26 We have reviewed 20 intraocular lym phoma patients examined and managed at our institu tion to attempt to delineate accuracy of vitreous studies and the effect oftreatment on this disease. Some ofthese cases have been reported previously. 3•15•21
MATERIALS AND METHODS Twenty patients were referred to the University of California, San Francisco; 13 were evaluated by one of us (DHC), and the diagnosis of an intraocular lym phoma was made on the basis of histologic or cytologic criteria in all cases. Initial patients studied between 1968 and 1975 did not have computed tomographic (CT) evaluations, the remainder did. All patients had a com plete physical examination, bone marrow biopsies, complete blood counts, and cerebrospinal fluid (CSF) cytology. In 14 cases, vitreous biopsies were performed. Both body and brain CT examinations with contrast were done on all patients examined after 1976. In seven patients studied before 1974, vitreous sam ples were obtained through the pars plana using a needle and syringe. In the remaining 13 patients, the choice ofa needle aspirate versus vitrectomy was predicated on the opacity of the vitreous. Four patients with minimal vit reous involvement and good vision (>20/60) had a pars plana aspirate with a 20-gauge needle to obtain a vitre ous specimen. In two of these four cases, core vitrecto mies were performed later because of vitreous clouding. In nine patients with more extensive vitreous involve ment, a core vitrectomy was performed. In these pa tients, an infusion port was sutured in place, and an MVR blade was used to make incisions for a light pipe and a vitrectomy instrument. Before placing the vitrec tomy instrument in the eye, approximately 1 ml of liq uid vitreous was aspirated with a 20-gauge blunt needle. No complications were noted as a result of aspiration. Cytologic specimens were handled in a standard manner. 27 •28 All CSF and vitreous specimens were pro cessed through a negative pressure, 5-~-tm millipore filter, and fixed overnight in 95% ethanol. They were stained with a modified Papanicolaou technique. Cytologic features analyzed included overall cellular ity, cell size, presence of necrotic debris, polymorphonu clear leukocytes, mitotic figures, nucleoli, the degree of nuclear membrane and chromatin irregularity, and the proportion of abnormal cells. In nine cases studied between 1980 and 1986, vitreous needle biopsies were divided in two parts and taken from the operating room to the laboratory for immedi ate cytologic and immunologic analysis. In three cases, a separate, second sample was simultaneously analyzed; this was obtained through the vitrectomy instrument and harvested from the balanced salt solution plus-spec imen reservoir. Immunologic evaluation of vitreous cells was per formed in three early cases using rosette techniques, and in six cases with a fluorescence-activated cell sorter 626
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(FACS IV, Becton Dickinson Co, Sunnyvale, CA) using dual-channel, two-color techniques. 29 - 31 Fluorescein isothyocyanate or phycoerythrin-conjugated mono clonal antibodies (a gift from Becton-Dickinson) were used including Leu 2a (T cytotoxic/suppressor cells), Leu 3a (T helper/inducer cells), Leu 4 (total T-cells), Leu 16 (total B-cells), Leu 11 (T suppressor cells, large granular lymphocytes, and natural killer cells), and IL-2 (activated T -cells). Treatment protocols have been modified over time, and not all patients received radiation therapy at the same institution. Generally, patients with combined eye and CNS disease were treated with a combination of intrathecal methotrexate and photon irradiation to the CNS and spinal cord.3•21
RESULTS Nineteen of 20 cases were diagnosed at our institu tion. The mean age of patients was 61 years (range, 35-82 years). Ocular symptoms, most commonly either floating spots or decreased vision, were the presenting sign of the disease in 13 cases. Seven of 20 patients initially presented with CNS symptoms before the dis covery of ocular disease; four had the diagnosis of a cerebral lymphoma confirmed before the diagnosis of the eye tumor. Eventually, 16 of 20 had evidence of CNS involvement. The interval between first ocular or nervous system symptoms and diagnosis was 0 to 60 months. There was a significant difference in the inter val between symptoms and diagnosis in the 11 patients examined before 1980 as compared with the 9 patients evaluated after that date; the mean interval in the first group was 24.3 months versus 5.8 months in the latter group (Student's t test; P < 0.006). No patient presented with systemic lymphoma; systemic malignancy devel oped in three patients between 18 and 36 months after the ocular diagnosis was established. In two of three patients, there was ocular, CNS, and systemic lym phoma. One patient had only ocular and systemic in volvement. Ocular involvement was bilateral in 18 of 20 cases; all patients had vitreous cells and in 15 there was evidence ofcellular anterior segment involvement (Table 1). Reti nal lesions were noted in 16 cases. In most patients, there was marked asymmetry in both cellularity and retinal lesions. Irregular, poorly defined, yellowish, or white retinal or chorioretinal lesions were typical as shown in Figure 1. Often it was not possible on the basis of clinical examination to determine whether these tumors were confined to a specific retinal, retinal pig ment epithelial, or choroidal layer. In two cases, a signif icant hemorrhagic retinal component was noted, and one patient had an exudative detachment. Four patients had no obvious retinal lesions; one had eye and CNS disease and died, two had only eye involvement and are alive, and one is alive after treatment for ocular and CNS lymphoma.
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Table 1. Clinical Parameters in 22 Patients with Primary Intraocular Lymphoma Parameters Vitreous cells Anterior segment cells Retinal, RPE, and choroidal lesions Bilateral eye disease Central nervous system involvement Mean age (yrs)
No. of Patients 20
15 16 18 16 61
RPE = retinal pigment epithelial.
Brain CT with contrast, using second- through fourth-generation scanners, demonstrated brain lesions in five cases; two patients had magnetic resonance image scans that mirrored the pathology noted on CT brain scan. In all lesions that were diagnosed on either CT or magnetic resonance imaging, a discrete tumor mass was noted. Results of CSF cytologic examination were posi tive in six cases. In one CT-positive case, results of the CSF cytologic examination were negative, and one pa tient with positive results of cytologic examination had a negative CT scan. Four cytologic features were characteristic for the diagnosis of intraocular lymphoma: irregular nuclear contours, lobation of nuclei, coarse irregular chromatin, and presence of nucleoli (Fig 2). Mitoses were occasion ally observed in intraocular lymphoma specimens, and necrotic material was sometimes present. Inflammatory cells were infrequent. In three patients with symmetrical disease, the diag nosis could not be made either prospectively or retro spectively on the initial vitreous biopsy. In one of these patients, the first eye had two separate biopsies (anini tial diagnostic procedure followed several months later by a therapeutic vitrectomy) with only inflammatory cells noted on both cytologic and immunologic evalua tions. A third vitreous biopsy at a later time established the diagnosis; retrospective analysis of the two earlier specimens was negative for malignancy. In the second patient, because of strong clinical suspicion and an equivocal CSF cytologic examination, the contralateral vitreous was removed l week later and a cytologic diag nosis of intraocular lymphoma was established. The third patient had been treated with radiation at another institution without a diagnosis, then referred with recur rent visual symptoms 2 years later. At that time, a sec ond vitreous biopsy was positive. In three cases, we compared vitreous cytologic detail from specimens removed directly from the eye with a 20-gauge needle versus material taken through the vi trectomy unit and obtained from the aspiration reser voir. Figures 3 and 4 demonstrate the loss of cellular detail that occurred when the specimen was obtained through vitrectomy instrumentation. The relative con tribution of the vitrectomy instrument versus maintain ing the cells for 30 to 60 minutes in a balanced salt plus reservoir is unclear.
Fig 1. Clinical photograph of intraocular lymphoma with typical cho rioretinal infiltrates.
Fig 2. Vitreous sample from patient showing typical lobation of nuclei, and coarse irregular chromatin.
Immunologic assessment of cell type was performed on multiple specimens from the nine cases studied. 15 Six specimens were not typeable with the reagents used, and defined as null cell lymphomas. Two specimens were polyclonal, and two consisted of probable T-cell neo plasms. In contrast to patients with benign forms of uveitis that usually have significant numbers of acti vated (IL-2 positive) intraocular T -cells, less than 1% of 627
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20 months (range, 1-31 months). The mean survival in living patients treated since 1978 is 41 months (range, 18-109 months); two of these patients have been fol lowed for less than 2 years after therapy.
DISCUSSION
Fig 3. Vitreous cells obtained from a 20-gauge needle.
Fig 4. Vitreous specimen from same case as Figure 3 obtained through a vitrectomy instrument. Both samples were processed in an identical manner simultaneously.
cells in the six diagnostic intraocular lymphoma speci mens studied were positiveY Follow-up and treatment data are summarized in Table 2. The radiation and chemotherapy protocols used with these patients have been described pre viously.3 Recent patients with eye and CNS disease have received 45 Gy of photon radiation to the eyes and whole-brain plus intrathecal methotrexate. Three of 11 patients treated before 1977 are alive. Systemic recur rences developed in two patients 7 and 4 years after initial diagnosis; after systemic chemotherapy, they re main in good health 3 and 4 years later. The interval between diagnosis and death in patients who died ofthis disease ranged from 5 to 39 months (mean, 15.8 months). Three of nine patients treated since 1978 have died; the mean interval between diagnosis and death was 628
Intraocular lymphoma, that is not a sequelae of a malignant systemic lymphoid tumor, is an unusual neo plasm with a predilection for the eye and CNS. Central nervous system tumor usually develops in most patients with this intraocular lymphoma; in the current study, this occurred in 16 of 20 patients (80%). This incidence of CNS lymphoma is slightly higher than noted in some reviews; however, the follow-up of our patients was complete, and the observation that late CNS disease de velops in some patients probably accounts for this dif ference.7·9 Similar to previous studies, we noted that most patients initially presented with ocular involve ment, and both vitreous cells and typical yellowish white retinal infiltrates were common. Although some investigators have stated that the involvement of uvea versus retina is more common when the lymphoma is associated with systemic versus CNS disease, this was not our uniform experience. 22·26 In four patients, there was no evidence ofa retinal or choroidal mass, and three other patients had somewhat atypical findings including an exudative detachment, hemorrhagic retinal changes, or neovascular glaucoma; others have noted similar findings. 10• 19·22·32 Often it is not possible to clinically de lineate a lesion as arising from a single layer (i.e., cho roid, retinal pigment epithelium, or retina). Vitreous biopsy could establish the diagnosis of intra ocular lymphomas in over 95% of patients. In a small study where we compared the sensitivity of cytologic with lymphocyte subset analysis, we noted that the former technique was more accurate. 15 We observed lymphocyte heterogeneity on immunologic analysis of lymphocyte surface markers in at least six of nine pa tients studied. 15 This finding limits the use of lympho cyte marker analysis as a method of diagnosing intra ocular lymphoma. The apparent lack of tumor mono clonality could be due to many causes. It is possible that a normal population of inflammatory cells is admixed with the tumor population to produce the heterogeneity observed. 33 ·34 In previous studies of intraocular lym phomas, an admixture of benign inflammatory cells has been noted. 5·17·35 ·36 Biclonal or triclonal populations of lymphoma cells can occur. 36 Newer Southern blot anal ysis can detect a much smaller percentage monoclonal population than is possible with the techniques we used; however, it is still quite difficult to do those studies on fine-needle aspiration biopsies, and it is costly. 33 ·37 ·38 The accuracy of a negative vitreous aspirate is uncer tain. In some cases, a single vitreous biopsy was not always adequate to establish a diagnosis. We have exam ined specimens from other institutions in which a false negative cytologic diagnosis occurred (unpublished data). In some of these cases, specimens were poorly
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prepared, whereas in others an inaccurate interpretation led to an incorrect diagnosis. In our experience, there was cellular degradation in three cases when specimens were obtained with vitrectomy instrumentation as com pared with samples from a needle and syringe. It is un certain whether loss ofcellular detail was from the irriga tion solution or the mechanical action of the vitreous cutter, but optimization ofcell preservation is important to establish the correct diagnosis. All of our cases had liquid vitreous secondary to both tumor and inflamma tion, and no apparent damage occurred from a fine-nee dle aspiration biopsy. In some cases, probably either a random sampling error or a relative lack of tumor cells at the time of vitreous biopsy resulted in a false-negative diagnosis. 38 In this series, three patients required more than one vitreous biopsy to establish the diagnosis. Vit reous biopsy and analysis of the vitrectomy fluid from the clinically more involved eye was not always diag nostic. Many reports have stressed the dismal prognosis of patients with intraocular lymphoma. In our initial radia tion study, eight of nine patients eventually died of their disease. 21 In a review of 68 patients, 45 (69%) died. 9 In 1981, we reported on long-term survival in three pa tients treated with a combination of radiation to the eyes and CNS plus adjunctive intrathecal chemotherapy. 3 Others have noted that these intraocular lymphomas are often sensitive to chemotherapy. 8•24•25 Our data demon strate improved survival when patients with intraocular and CNS lymphoma are treated with a combination of intrathecal chemotherapy and both eye and whole-brain irradiation to 40 to 45 rad in 25 to 30 fractions. Seven of nine patients treated since 1978 are alive. The optimum management of these cases with com bined eye and CNS disease is uncertain. We have dem onstrated that many such patients can be salvaged with a combination ofbrain-ocular irradiation plus intrathecal chemotherapy. In general, patients with gross CNS dis ease that is symptomatic do poorly, whereas asympto matic patients with either only small foci of CNS lym phoma demonstrable with CT/magnetic resonance imaging, positive CSF cytologies, or no CNS disease ap pear to respond much better to treatment. Unfortu nately, almost 10% of such patients have experienced obvious CNS morbidity after aggressive therapy, and recurrent disease has developed in two patients outside ofthe eye or CNS several years later. In both ofthe latter cases, systemic chemotherapy appears to have produced long-term survivals without further recurrences. The management of patients with only ocular in volvement remains an enigma. One such patient re ported by Hogan and Klingele26 had only enucleation and died of other causes; however, there was tumor present in other sites at postmortem examination. Other authors have anecedotal reports of patients cured with only enucleation. 4 •25 In this series, two patients with iso lated ocular involvement had only ocular radiation with no recurrent disease 24 and 109 months after treatment. More follow-up is necessary, since the interval between the diagnosis of ocular lymphoma and development of
Table 2. Therapies and Their Effect*
Therapy Ocular and CNS radiation Ocular radiation alone Eye/CNS radiation plus chemotherapy* Systemic chemotherapy alone Enucleation alone
Alive (mean survival, mos) 0 2 (24, 109) 8 (122, 140, 96, 18, 48, 18, 29, 30)
Died of Tumor (mean survival, mos) 4 (1, 24, 9, 39) 0 4 (5, 21, 7, 31) 1 (12)
10
1 (9)
CNS = central nervous system. * All surviving patients in this group received radiation to the eye and brain plus intrathecal chemotherapy; three patients in deceased group received simi liar chemotherapy. Some patients received systemic chemo therapy for extra-CNS disease.
CNS disease can have a latency of as long as 10 years. 39•40 It is apparent that even with modern diagnos tic modalities, it is difficult to correctly diagnose this malignancy; however, our series shows that as the oph thalmic community has recognized this tumor, the in terval between symptom onset and correct diagnosis has significantly diminished. Since some of these patients can be effectively treated, it is of paramount importance to make an early diagnosis.
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12. Taylor CR. Russell R, Lukes RJ, Davis RL. An immunohistological study of immunoglobulin content of primary central nervous system lymphomas. Cancer 1978; 41 :2197-205. 13. Varadachari C, Palutke M, Climie ARW, et al.lmmunoblastic sarcoma (histiocytic lymphoma) of the brain with B cell markers. J Neurosurg 1978; 49:887-92. 14. Warnke R, Miller R, Grogan T, et al. Immunologic phenotype of 30 patients with diffuse large-cell lymphoma. N Engl J Med 1980; 303:293-300. 15. Char DH, Ljung B-M, Deschenes J, Miller TR. Intraocular lymphoma: immunologic and cytologic analysis. Br J Ophthalmol (in press). 16. Michels RG , Knox DL, Erozan YS , Green WR . Intraocular reticulum cell sarcoma: diagnosis by pars plana vitrectomy. Arch Ophthalmol 1975; 93:1331-5. 17. Kennerdell JS, Johnson BL, Wisotzkey HM. Vitreous cellular reaction: association with reticulum cell sarcoma of brain. Arch Ophthalmol 1975; 93:1341-5. 18. Kaplan HJ, Meredith TA, Aaberg TM, Keller RH. Reclassification of intraocular reticulum cell sarcoma (histiocytic lymphoma): immuno logic characterization of vitreous cells. Arch Ophthalmol 1980; 98:707-10. 19. Michelson JB, Michelson PE, Bardin GM, Chisari FV. Ocular reticulum cell sarcoma: presentation as retinal detachment with demonstration of monoclonal immunoglobulin light chains of the vitreous cells. Arch Ophthalmol 1981; 99:1409-11 . 20. Deschenes J, Freeman WR, Char DH, Garovoy MR. Lymphocyte subpopulations in uveitis. Arch Ophthalmol1986; 104:233-6. 21. Margolis L, Fraser R, Lichter A, Char DH. The role of radiation therapy in the management of ocular reticulum cell sarcoma. Cancer 1980; 45:688-92. 22. Kim EW, Zakov ZN, Albert DM, et al. Intraocular reticulum cell sar coma: a case report and literature review. Albrecht von Graefes Arch Klin Exp Ophthalmol 1979; 209:167-78. 23. Givner I. Malignant lymphoma with ocular involvement: a clinico pathologic report. Am J Ophthalmol 1955; 39:29-32. 24. Baumann MA, Ritch PS, Hande KR , et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986; 57:1273-5. 25. Sullivan SF, Dallow RL. Intraocular reticulum cell sarcoma: its dra matic response to systemic chemotherapy and its angiogenic poten tial. Ann Ophthalmol 1977; 9:401-6.
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