Acquired Immunodeficiency Syndrome-Related Primary Intraocular Lymphoma Constance A.

Stanton, MD;

D.

Bryan Sloan III, MD;

A 37-year-old man with acquired immunodeficiency syndrome and cytomegalovirus retinitis developed primary in\s=b\

traocular and central nervous system lymphoma. Intraocular involvement was documented before death with vitrectomy. Autopsy demonstrated the presence of cytomegalovirus retinitis in the right eye and lymphoma in both eyes and the brain. We believe this is the first report of autopsy-confirmed primary intraocular lymphoma in a patient with the acquired

immunodeficiency syndrome. (Arch Ophthalmol. 1992;110:1614-1617)

"VTon-Hodgkin's lymphoma, -^

both

pri-

mary in the central nervous sys¬ tem (CNS) and systemic, is a wellknown complication of the acquired

immunodeficiency syndrome (AIDS).1

Ocular involvement may be seen with primary CNS lymphoma,2 and AIDSrelated systemic lymphomas have an increased incidence of extranodal in¬ volvement compared with lymphoma seen in immunocompetent patients.1 Patients with AIDS are, therefore, at risk of developing intraocular lym¬ phoma. Only a few cases of AIDSrelated intraocular lymphoma have been reported.8"' Of these, only the case reported by Schanzer et al3 was de¬ scribed in detail, and none of the previAccepted

for publication July 31, 1992. From the Departments of Pathology (Dr Stanton) and Ophthalmology (Drs Stanton, Sloan, Slusher, and Greven), Bowman Gray School of Medicine, Winston-Salem, NC. Presented in part at the Georgiana Dvorak Theobald Society, Tucson, Ariz, May 15, 1992. Reprint requests to the Department of Ophthalmology, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1033 (Dr

Greven).

M. Madison

Slusher, MD; Craig

M.

Greven,

ous descriptions presented confirma¬ tion of the diagnosis by pathologic examination of the eyes and brain. The case reported herein is that of a patient with AIDS known to have cytomegalovirus (CMV) retinitis who later devel¬ oped lymphoma in both eyes and the brain. The intraocular involvement was demonstrated before death in the right eye with vitrectomy and in both eyes at

autopsy.

REPORT OF A CASE A 37-year-old man diagnosed as having AIDS in May 1989 developed the systemic complications of Pneuniocystis carinii pneumonia, shigellosis, and disseminated Mycobacterium avium-intracellulare infec¬ tion. Screening ophthalmic examinations were negative for infectious retinopathy un¬ til April 1991, when the patient presented with visual acuities of 20/20 OD and 20/20 OS and typical CMV retinitis in the temporal midzone of his right eye; his left retina was normal. He received ganciclovir sodium in¬ duction (325 mg intravenously twice a day for 14 days) followed by maintenance ther¬ apy (440 mg intravenously five times per week), and the CMV retinitis became inac¬ tive. The patient's condition remained stable until October 1991, when he presented with decreased vision in his right eye, memory disturbance, and disorientation. Visual acu¬ ity was hand motions in the right eye and 20/30 OS. Slit-lamp examination results were normal in both eyes. Funduscopic examina¬ tion showed 3+ vitreous cells and debris ob¬ scuring view of the retina of the right eye. The left eye had peripheral retinal hemor¬ rhages but was otherwise normal. Cranial magnetic resonance imaging disclosed mul¬ tiple enhancing brain lesions believed to be consistent with lymphoma or toxoplasmosis, for which the patient was treated with cor¬ ticosteroide and antibiotics.

Diagnostic

and

therapeutic vitrectomy

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MD

performed in November 1991. After the vitreous debris was removed, the retina was noted to have burned-out CMV retinitis with¬ out other abnormalities. Cytologie examina¬ tion of the vitrectomy specimen revealed marked atypical cells in clusters (Fig 1) thought to strongly suggest a diagnosis of lymphoma. A stereotactic brain biopsy spec¬ imen was nondiagnostic, showing reactive astrocytes, macrophages, and a few scattered was

benign-appearing lymphocytes; no neoplastic cells, Toxoplasma, fungi, or bacteria were seen. Lumbar puncture yielded only a few mononuclear cells that were not atypical (white blood cell count, 0.006 X107L). The cerebrospinal fluid protein level, glu¬ cose level, cultures, and serologie test results for cryptococcus and toxoplasma were unre¬ markable. The patient refused an open brain biopsy and other therapy and died at home in January 1992 after a progressively downhill course. An autopsy, including examination of the eyes and brain, was performed. PATHOLOGIC FINDINGS

The

autopsy showed non-Hodgkin's cell type, involving

lymphoma, large multiple sites in

the brain and both eyes, with small extraneural foci in the right middle lobe of the lung and dia¬ phragm. Other findings included CMV retinitis of the right eye, bilateral acute patchy bronchopneumonia, human im¬ munodeficiency virus (HIV) nephropathy, nodular hyperplasia of the pros¬ tate, and mild testicular atrophy. Gross examination of the right eye showed a raised, yellow-white lesion 3 mm in greatest dimension 1 mm from the optic nerve head. Examination of the left eye revealed an irregular, some¬ what nodular white lesion 5 mm in greatest dimension located in the su-

perotemporal region approximately 6 mm posterior to the ora serrata and 10 mm anterior to the optic nerve head.

Fig 1.—Vitrectomy specimen. Large, atypical

cells with scant cytoplasm, irregular nuclear contours, and prominent nucleoli are seen

(Papanicolaou's stain, original magnification X312.5).

Fig 4.—Autopsy specimen from the left eye. Tumor cells are located below the retinal pig¬ ment epithelium (RPE) but spare the choroid. Tumor cells are also present in the subretinal space above the RPE (as well as in the ret¬ ina outside the field of view in this photo¬

Fig 2.—Autopsy specimen from the left eye. Intraretinal tumor cells with large nuclei, ir¬ regular nuclear contours, and prominent nu¬ cleoli similar to those seen in the vitrectomy specimen are seen (hematoxylin-eosin, orig¬ inal magnification X312.5).

Fig 3.—Autopsy specimen from the right eye. Intraocular lymphoma with tumor cells sur¬ rounding superficial retinal vessels are seen (hematoxylin-eosin, original magnification X31.25).

Fig 5.—Autopsy specimen

Fig 6.—Autopsy specimen from the brain. Tumor cells similar to those seen in the vitrectomy specimen and in the retinas are

from the brain. Perivascular distribution of tumor cells typical of primary central nervous system lymphoma is seen (hematoxylin-eosin, original magnifi¬ cation X31.25).

tion

retinal vessels (Fig 3). The tumor cells infiltrated all layers of the retina. In some areas the bulk of the tumor occu¬ pied the subretinal space and/or was beneath the retinal pigment epithelium (Fig 4). However, Bruch's membrane was intact and no tumor invaded the choroid. The optic nerves were pale and exhibited mild gliosis. No tumor cells were seen in the subarachnoid space surrounding the optic nerves or in the optic nerve parenchyma. The anterior structures of both eyes were unremark¬ able. The brain weighed 1520 g fixed. On sectioning, multiple yellow-gray lesions involving both cerebral hemispheres were seen, as well as a lesion in the left cerebellar hemisphere. The biopsy site was well demarcated, yellow, and hard.

Microscopically, lymphoma involved al¬ examined, including the cerebral hemispheres, midbrain, pons, medulla, and cerebellum. Tumor cells were also present in the leptomeninges. The tumor cells had the angiocentric distribution characteristic of primary CNS lymphoma (Fig 5) and were morphologically identical to those noted in the eyes (Fig 6). They exhib¬ ited immunoreactivity for L26 (DakoCD20, a T-cell antigen, Biotest Diag¬ nostics Corp, Fairfield, NJ), but no reactivity with MB2 (a B-cell antigen that does not react with plasma cells, Biotest Diagnostics Corp) or UCHL1 (Dako-CD45, a pan T-cell antigen, Dako), a staining pattern consistent with large cell AIDS-related lym¬ phoma.6 No clear-cut monoclonality

(hematoxylin-eosin, original magnifica¬ X312.5).

seen

graph) (hematoxylin-eosin, original magnifi¬ X62.5).

cation

Microscopie examination of the right eye showed focal retinal necrosis unac¬ companied by inflammation. Large in¬ tranuclear viral inclusions were seen as well as eosinophilic aggregates of necrotic cell remnants and microscopic calcifications. Immunoreactivity to an¬ tibodies against CMV but not herpes simplex type 1 or 2 was seen in super¬ ficial and deep layers of the retina but not the choroid. No CMV retinitis was found in numerous sections of the left eye. Neoplastic cells morphologically identical to those seen in the vitrectomy specimen were identified in both eyes (Fig 2). The pattern of tumor infiltra¬ tion in both eyes was similar. At the periphery of the tumor the cells were located in a perivascular dis¬ tribution surrounding the superficial

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most all sections

with antibodies to

light

or

(Dako) was seen.

chains

Benign-appearing lymphocytes and plasma cells were admixed with the tu¬ mor cells. Necrosis, accompanied by acute inflammatory cells, and reactive astrocytosis were prominent. The bi¬ opsy site consisted of

an area

of

co¬

agulation necrosis surrounded by reac¬ tive astrocytes, macrophages, and scattered benign-appearing lympho¬ cytes, but no lymphoma was identified. These findings were consistent with those of the previous brain biopsy. No evidence of progressive multifocal leukoencephalopathy, toxoplasmosis, M avium-intracellulare, or primary HIV infection identified.

of the

brain

was

COMMENT

This report presents

a case

illustrat¬

ing two ophthalmologic conditions seen in patients with AIDS, ie, CMV retini¬ tis and primary ocular/CNS lymphoma, diagnosed before death and confirmed at autopsy. Since lymphoma is the sub¬ ject of this discussion, CMV retinitis will not be dealt with here. The clinical and pathologic features of this case are consistent with those described

elsewhere.79 Ocular lymphoma

can

mimic other

ophthalmologic conditions, especially inflammatory10 or vascular diseases.4 The first description of lymphoma mas¬ querading as uveitis was reported by Cooper and Riker11 in 1951 in a 27-year-

old man who died 11 months later with disseminated systemic lymphoma. In the immunocompetent patient, ocular lymphoma usually presents in the sixth or seventh decade as unilateral or bilat¬ eral blurred vision or floaters due to anterior uveitis and/or vitreitis and/or chorioretinitis. Complications, such as retinal detachment, hemorrhage in the retina or vitreous, neovascular glau¬ coma, or optic nerve edema, can de¬ velop.10 A classic scenario in which the diagnosis of lymphoma should be con¬ sidered is that of a patient older than age 40 years with uveitis of unknown cause that is unresponsive to conven¬ tional therapy. Intraocular lymphoma may arise ei¬ ther as a primary process or as one site of involvement in disseminated sys¬ temic lymphoma. Ocular disease is con¬ sidered a harbinger of disease else¬ where, particularity the brain, since isolated eye involvement is the least common pattern of ocular lymphoma. The case presented herein and the case of Parver and Font,12 also diagnosed with vitrectomy and confirmed at au¬ topsy but in a non-HIV-infected pa-

tient,

are examples of primary ocular lymphomas and fit the general trend that primary ocular lymphoma usually

nocompetent patient has

infiltrates the retina and spares the choroid, while metastatic systemic lym¬ phoma usually involves the uvea.13"15 A strong association between pri¬ mary ocular lymphoma and primary CNS lymphoma exists; 80% of the pa¬ tients with primary ocular lymphoma in one study16 had or developed CNS dis¬ ease. Primary CNS lymphomas are well known for being multicentric in the nervous system,17 and in one study of primary CNS lymphoma, ocular dis¬ ease was noted in five (19%) of 27 of cases.18 Primary ocular lymphoma is also a multicentric process since bilat¬ eral ocular disease has been reported in up to 90% of cases.16 This leads some to consider that the retina and brain, because of their embryologie relationship, are in a common "zone of susceptibility"14 and that primary ocu¬ lar and primary CNS lymphoma are the same disease process. Ocular in¬ volvement is thus seen as a manifes¬ tation of disseminated nervous system

course, and is seen in younger pa¬ tients.22 Untreated, the mean survival may be as low as 42 days.2 Whole-brain radiation (including the posterior or¬ bits) is currently recommended for AIDS-related CNS lymphoma.2 Early systemic and intrathecal chemotherapy appears to be beneficial in immunocom¬ petent patients.218 It may be justified in patients with AIDS with high CD4 counts and no evidence of opportunistic infection,2 but the benefit has yet to be assessed by prospective studies. Most patients undergo treatment of CNS lymphoma only to die of another AIDSrelated condition, often in the CNS.23 Very few cases of primary ocular lymphoma associated with AIDS have been described.35 Schanzer et al3 re¬ ported a case of a 42-year-old man known to be serologically positive for HIV whose ocular symptoms included floaters, loss of central vision, flashing lights, and foreign-body sensation. Ex¬ amination revealed retinochoroidal le¬ sions in both eyes. The diagnosis of lymphoma was made with vitrectomy. The cerebrospinal fluid cytologie exam¬ ination was later positive for lym¬ phoma, and imaging studies revealed a clincally asymptomatic lesion in the cer¬ ebellum. Radiation was administered to both globes and the brain, with subse¬ quent regression of the eye lesions. The patient died 18 months later, with sei¬ zures and coma. No autopsy was per¬ formed. Gass and Trattler,4 in their report on vascular lesions associated with in¬ traocular lymphoma, mentioned a case of a patient with AIDS with acute branch retinal artery occlusion overly¬ ing a large zone of irregular solid de¬ tachment of the retinal pigment epithe¬ lium and retinal infiltration. The diagnosis of lymphoma was based on a biopsy of a brain lesion. The masses in the eye disappeared with radiation. No further details were given. Duker et al5 described two HIV-infected patients with intraocular lymphoma diagnosed by vitreous biopsy who were thought to have intraocular infections based on clinical examination. Of note is that our patient and those of Schanzer et al3 and Gass and Trattler4 all had concurrent CNS lymphoma. (No information about the condition of the brain in the cases of Duker et al5 was provided.) The incidence of ocular lymphoma in AIDS is unknown. In one series, includ¬ ing clinical examination of 200 patients with AIDS and postmortem examina¬ tion of the eyes of 25 patients,8 no examples of intraocular lymphoma

disease.2,18

Because of the multicentricity of pri¬ mary ocular/CNS lymphoma, some have suggested that radiation should be administered empirically to both eyes and the CNS in any immunocompetent patient with lymphoma documented in one eye.19 Others20·21 advocate a more cautious approach to prophylactic irradiation given the lack of prospec¬ tive trials addressing this issue. The use of chemotherapy as a means to treat the multicentricity of primary CNS lymphoma is well established,2 but it is controversial for ocular

lymphoma.2,19·21

The incidence of primary CNS lym¬ phoma is increased in patients with AIDS compared with immunocompetent patients, with the risk for patients with AIDS being increased about 100-fold.2 In the general population primary CNS lymphomas make up less than 1% of in-

tracranial tumors and about 2% of all lymphomas.17 In the AIDS population about 5% of patients are affected1 and

lymphoma is second only to toxoplasmo-

sis as the cause of mass lesions in the brain.22 The incidence of CNS lymphoma is increasing in both the immunocompe¬ tent setting and the setting of AIDS. Since CNS lymphoma is considered a relatively late manifestation of AIDS (although it may be the presenting sign of AIDS), the incidence may be ex¬ pected to continue to rise as more peo¬ ple enter the late stages of the disease and survive longer with treatment.1 Central nervous system lymphoma in AIDS compared with that in the immu-

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a higher inci¬ multicentricity, is clinically more advanced, runs a more fulminant

dence of

found; one orbital lymphoma was noted in the autopsy part of the series. In another autopsy series of 35 patients, no case of intraocular lymphoma was found. This suggests that either the in¬ cidence of ocular lymphoma in AIDS is not as great as that of CNS lymphoma or eye involvement is going undetected or unreported. The tendency for in¬ traocular lymphoma to mimic other dis¬ eases that required different treat¬ ments, the multicentricity of primary ocular/CNS lymphoma, and the poor prognosis for patients with AIDS with untreated lymphoma suggest that early and accurate detection of intraocular lymphoma may be beneficial not only for early treatment of eye disease but also for CNS disease, the latter being the source of significant mortality. A definitive antemortem diagnosis of intraocular lymphoma can be made via a biopsy of the vitreous (either with as¬ were

piration or vitrectomy). Presumptive diagnoses of intraocular tumor have also been made by finding malignant cells in the cerebrospinal fluid and by biopsy of associated brain lesions. The

of vitreous biopsies for the detection of lymphoma has not been established. Multiple examples of negative initial biopsy specimens in symptomatic patients exist and, thus, the need for repeated examin¬ ations in suspicious cases has been

sensitivity

emphasized.18·24 In CNS

addition, patients with primary lymphoma who have no ophthal¬ mologic symptoms have been reported to have positive vitreous biopsy speci¬ mens,18 stressing the need for thorough ophthalmologic examination in patients known to have CNS lymphoma. Vitre¬ ous biopsies and lumbar punctures have

been advocated as means to avoid cra¬ nial surgery in nonimmunocompromised patients.20 However, given the variety of CNS diseases that occur with AIDS and that patients with AIDS may have multiple simultaneous neuropathologic processes, direct evaluation of brain disease may be necessary, espe¬ cially if the response to therapy is not as

expected.1

Primary ocular/CNS lymphomas are usually high-grade, B-cell lymphomas of large cell type (formerly reticulum cell sarcoma) or small, noncleaved (Burkitt's non-Burkitt's) type.1 Cytologie fea¬

or

tures consistent with lymphoma include cellular pleomorphism, round to oval nu-

elei with irregular or lobated contours and folded nuclear membranes, coarse chromatin, fingerlike nuclear projec¬ tions, prominent and often multiple nu¬ cleoli, and scant cytoplasm2426 (Figs 1,2, and 4). Lymphoma cells are usually noncohesive, but clumping on the vitreal fibrils may occur (as it did in this case) if vitreal involvement is marked.25 This may make the distinction between lym¬ phoma and carcinoma difficult. Immunohistochemical studies can be attempted if enough material is available and, in prin¬ ciple, should show staining with B-cell markers and monoclonality using anti¬ bodies to and light chains,27 but the results in individual cases may vary.6·17·24 The presence of inflammatory cells ad¬ mixed with tumor cells may further com¬ plicate interpretation of immunocytochemical results. Some believe, there¬ fore, that cellular morphological features are more reliable for diagnosis than immunotyping.24 Polymerase chainreaction technology, which amplifies cel¬ lular DNA content, may prove useful in analyzing small specimens, such as vitre¬ ous biopsy specimens, as more is discov¬ ered about the molecular pathogenesis of primary ocular/CNS lymphoma.27 References 1. Levine AM. Epidemiology, clinical characteristics, and management of AIDS-related lymphoma. Hematol Oncol Clin North Am. 1991;5:

331-342. 2. Hochberg FH, Loeffler JS, Prados M. The therapy of primary brain lymphomas. J Neurooncol. 1991;10:191-201. 3. Schanzer MC, Font RL, O'Malley RE. Primary ocular malignant lymphoma associated with the acquired immunodeficiency syndrome. Oph-

thalmology. 1991;98:88-91.

4. Gass JDM, Trattler HL. Retinal artery obstruction and atheromas associated with non\x=req-\ Hodgkin's large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol. 1991;109:1134-1139. 5. Duker JS, Fischer DH, Davis JL. Non\x=req-\ Hodgkin's lymphoma of the posterior segment complicating human immunodeficiency virus (HIV) infection. Presented at the annual meeting of the American Academy of Ophthalmology; 1991; Anaheim, Calif. Abstract of scientific poster 122. 6. Hamilton-Dutoit SJ, Pallesen G, Franzmann MB, et al. AIDS-related lymphoma: histopathology, immunophenotype, and association with Epstein-Barr virus as demonstrated by in situ nucleic acid hybridization. Am J Pathol. 1991;138: 149-163. 7. Heinemann M-H. Characteristics of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Am J Med. 1992;92: 12S-16S. 8. Jabs DA, Green WR, Fox R, Polk BF, Bartlett JG. Ocular manifestations of acquired immune de-

ficiency syndrome. Ophthalmology.

1989;96:

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1092-1099. 9. Pepose JS, Holland GN, Nestor MS, Cochran AJ, Foos RY. Acquired immunodeficiency syndrome: pathogenic mechanisms of ocular disease.

Ophthalmology. 1985;92:472-484. 10. Corriveau C, Easterbrook M, Payne D. Lymphoma simulating uveitis (masquerade syndrome). Can J Ophthalmol. 1986;21:144-149. 11. Cooper EL, Riker JL. Malignant lymphoma of the uveal tract. Am J Ophthalmol. 1951;34:1153\x=req-\

1158. 12. Parver LM, Font RL. Malignant lymphoma ofthe retina and brain: initial diagnosis by cytologic examination of vitreous aspirate. Arch Ophthalmol. 1979;97:1505-1507. 13. Klingele TG, Hogan MJ. Ocular reticulum cell sarcoma. Am J Ophthalmol. 1975;79:39-47. 14. Qualman SJ, Mendelsohn G, Mann RB, Green WR. Intraocular lymphoma: natural history based on a clinicopathologic study of eight cases and a review of the literature. Cancer. 1983;52:878\x=req-\ 886. 15. Vogel MH, Font RL, Zimmerman LE, Levine RA. Reticulum cell sarcoma of the retina and uvea. Am J Ophthalmol. 1968;66:205-215. 16. Char DH, Ljung B-M, Miller T, Phillips T. Primary intraocular lymphoma (ocular reticulum cell sarcoma): diagnosis and management. Ophthal-

mology. 1988;95:625-630.

17. Russell DS, Rubinstein LJ. Pathology of Tumours of the Nervous System. 5th ed. Baltimore, Md: Williams & Wilkins; 1989:592-608. 18. DeAngelis LM, Yahalom J, Heinemann M-H, Cirrinicione MS, Thaler HT, Krol G. Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology. 1990;40:80-86. 19. Trudeau M, Shepherd FA, Blackstein ME, Gospodarowicz M, Fitzpatrick P, Moffatt RP. Intraocular lymphoma: report of three cases and review of the literature. Am J Clin Oncol. 1988;11: 126-130. 20. Rockwood EJ, Zakov ZN, Bay JW. Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). J Neurosurg. 1984;61: 369-374. 21. Siegel MJ, Dalton J, Friedman AH, Strauchen J, Watson C. Ten-year experience with primary ocular 'reticulum cell sarcoma' (large cell non-Hodgkin's lymphoma). Br J Ophthalmol. 1989; 73:342-346. 22. So YT, Chouciar A, Davis RL, et al. Neoplasms of the central nervous system in acquired immunodeficiency syndrome. In: Rosenblum ML, Levy RM, Bredesen DE, eds. AIDS and the Nervous System. New York, NY: Raven Press; 1988: 285-300. 23. Goldstein JD, Dickson DW, Moser FG, et al. Primary central nervous system lymphoma in acquired immunodeficiency syndrome: a clinical and pathologic study with results of treatment with radiation. Cancer. 1991;67:2756-2765. 24. Ljung B-M, Char D, Miller TR, Deschenes J. Intraocular lymphoma: cytologic diagnosis and the role of immunologic markers. Acta Cytol. 1988;32: 840-847. 25. Michels RG, Knox DL, Erozan YS, Green WR. Intraocular reticulum cell sarcoma: diagnosis by pars plana vitrectomy. Arch Ophthalmol. 1975; 93:1331-1335. 26. Scroggs MW, Johnston WW, Klintworth GK. Intraocular tumors: a cytopathologic study. Acta

Cytol. 1990;34:401-408.

27. Davis JL, Solomon D, Nussenblatt RB, Palestine AG, Chan C-C. Immunocytochemical staining of vitreous cells: indications, techniques, and results. Ophthalmology. 1992;99:250-256.

Acquired immunodeficiency syndrome-related primary intraocular lymphoma.

A 37-year-old man with acquired immunodeficiency syndrome and cytomegalovirus retinitis developed primary intraocular and central nervous system lymph...
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