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Iris Involvement in Primary Intraocular Lymphoma
SURVEY OF OPHTHALMOLOGY VOLUME 44 • NUMBER 6 • MAY–JUNE 2000
CLINICAL PATHOLOGIC REVIEW DAVID APPLE AND MILTON BONIUK, EDITORS
Iris Involvement in Primary Intraocular Lymphoma: Report of Two Cases and Review of the Literature Gisela Velez, MD, MPH,1 Marc D. de Smet, MD,1,2 Scott M. Whitcup, MD,1 Michael Robinson, MD,1 Robert B. Nussenblatt, MD,1 and Chi-Chao Chan, MD1 1 2
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA, and Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Abstract. Non-Hodgkin’s lymphoma involves ocular tissues either as a primary tumor or as secondary metastasis from systemic disease. Diagnosis is based on the identification of malignant cells in the eye by biopsy. Although primary intraocular lymphoma cells have been identified in the optic nerve, ciliary body, and iris of a small number of patients by histopathology, these sites of infiltration have rarely been observed on clinical examination. We studied clinical and histopathological findings of two patients with iris infiltration by primary intraocular lymphoma and reviewed the findings of 163 cases reported in the literature. (Surv Ophthalmol 44:518–526, 2000. © 2000 by Elsevier Science Inc. All rights reserved.) Key words. iris • large B-cell lymphoma • lymphoma • non-Hodgkin’s lymphoma
Primary intraocular lymphoma, previously known as reticulum cell sarcoma, is thought to have been first reported by Cooper and Ricker in 1951.9 The disease occurs mostly in middle-aged and older adults, although patients as young as 15 years have been reported.36,38 Two clinically distinct forms of non-Hodgkin’s lymphoma can affect the eye. NonHodgkin’s lymphoma of the central nervous system (NHL-CNS) which includes primary intraocular lymphoma (PIOL), arises from the brain, spinal cord, leptomeninges, or eye.59 Systemic spread outside the CNS rarely occurs; it is reported in fewer than 10% of autopsies.19,32 Systemic non-Hodgkin’s lymphoma, unlike NHL-CNS, can metastasize to the eye through the choroidal circulation. This is suspected to be the situation in the case reported by Cooper and Ricker.9 Patients with non-Hodgkin’s lymphoma of the central nervous system often present with ocular dis-
ease before the development of neurologic involvement. The most common ocular symptoms include blurred vision and floaters; redness and pain are rare. Although the visual acuity may be decreased, it is usually better than would be expected from clinical examination. Table 1 summarizes the clinical findings of 163 cases of NHL-CNS of the eye reported in the literature. Vitritis was the most common finding, present in 66% of patients (Table 2). Anterior chamber cells were found in 43%, and cream-colored subretinal yellow infiltrates were reported in 41%. Diagnosis of NHL-CNS or primary intraocular lymphoma is based on the identification of malignant cells in the eye by vitreous biopsy or biopsy of other ocular tissues, such as a chorioretinal biopsy.59 Typical lymphoma cells are large with scanty basophilic cytoplasm, hypersegmented nuclei, and multiple nucleoli. Vitreous biopsy, however, usually contains a small number 518
© 2000 by Elsevier Science Inc. All rights reserved.
0039-6257/00/$–see front matter PII S0039-6257(00)00118-1
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IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA TABLE 1
Case Reports of Primary Intraocular Lymphoma With Associated Clinical and Histopathologic Findings First Author 56
Vogel Neault33 Appen2 Barr3 Klingele23 Minckler31 Kim20 Parver34 Rosenbaum44 Simon48 Wagoner57 Michelson30 Sloas49 Raju39 Qualman38 Gass18 Kline22 Purvin37 Rockwood43 Lang25 Corriveau10 Kirmani21 Scherfig45 Char7 Kuming24 Trudeau53 Siegal47 de Smet12 Strauchen51 Lopez26 Ridley41 Allinson1 Peterson36 Matsuo27 Pavan35 Valluri55 Soussain50 Ciulla8 Fishburne16 Ursea54 Shen46 Matsuo28 Buggage5 Rivero42 Total
No. of IR/SR Perivascular Posterior Patients Vitritis Infiltrates Infiltrates AC Cells/KPs Synechiae 6 7 1 3 7 1 1 1 1 3 1 1 1 1 5 3 1 1 3 1 1 1 1 9 1 2 14 1 6 1 5 1 24 1 1 3 8 1 4 13 3 10 1 2 163
4 7 1 3 7 1* 1 1* 1 3 1 1 1 1* 1* 2
6* 1
3*
2 6 1 1* 2 1*
6 3 1 1 7 1*
ON
Iris
Posterior and Anterior
1* 1
2* 3 1 1 7 1
2* 1*
1* 1*
CB
1* 1 1
1 1
1* 1
1 1* 5* 3
1*
5*
1* 1*
3* 1 1 1
3 1* 1 1 1 9 1 1 14 1 6 1 5 1 21 1 1 3 8 1 4 10‡ 2* 7 1 2 107
3 1* 1 1 1 6 1 2 7 1 2 1 4
1 1 1 5
1
1‡
1
1‡
? 5
1 3 1 1
1*
1 1 1
1 3 1
1 1 1 8 1 3 3‡ 3* 7 1 2* 66
1†
3 1 6 1
3 1 6
1† 1 1
1 2
1 6 1
1 ? 1 4‡ 2
1 1 19
9 1 1 70
1‡
2 (1†) 5
20
5
1 1 37
7
IR/SR ⫽ intraretinal and subretinal; AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; ON ⫽ optic nerve; CB ⫽ ciliary body. * Confirmed by histopathology. † No history of surgical intervention. ‡ Suspected clinically and by ultrasonography.
of these atypical cells. Most of the biopsy material is reactive lymphocytes, histiocytes, debris, and fibrinous material, particularly in the early stage of the malignancy. Furthermore, the malignant cells are extremely fragile. Cell viability can be increased by adding tissue culture medium (RPMI-1640, Rosewell Park Memorial Institute, Mediatech, Inc., Herndon, VA, USA) en-
riched with 10% fetal calf serum to the initial undiluted vitreous specimen.59 In addition, the person handling the specimen must take care to minimize cell lysis. Immunohistochemistry performed on suspicious cells aids the diagnosis, because the majority of primary intraocular lymphomas are of B-cell lineage.
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TABLE 2
Clinical Characteristics of Documented Case Reports With Primary Intraocular Lymphoma Characteristic Vitritis AC cells/KPs IR/SR Infiltrates Posterior and Anterior ON Perivasculitis Iris CB
No.
%
107 70 66 37 18 19 5 7
66 43 41 23 11 12 3 4
AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; IR/ SR ⫽ intraretinal and subretinal; ON ⫽ optic nerve; CB ⫽ ciliary body.
The finding of B-cell markers with a kappa or lambda light chain monoclonal response confirms the diagnosis. In patients who do not demonstrate a dense vitritis but do have the subretinal infiltrates consistent with the disease, a chorioretinal biopsy can be taken, or the subretinal space can be flushed with saline and the aspirate sent for pathologic examination.4,21,46 A typical chorioretinal biopsy will show malignant cells between Bruch’s membrane and the retinal pigment epithelium (RPE). While reactive cells can be seen in the retina, their numbers are limited. In the choroid, this reaction is much more significant.5,20,23,26,34 Though primary intraocular lymphoma cells have been identified in the optic nerve, ciliary body, and iris of a small number of patients by histopathology, these sites of infiltration have rarely been observed on clinical examination. Iris and ciliary body infiltrations, in particular, have been confirmed only after enucleation of eyes or on postmortem examination.3,39,56,58 Infiltration of iris and ciliary body by tumor originating in the eye or brain has, therefore, rarely been documented. We present the clinical and histopathologic findings of two patients with iris infiltration by primary intraocular lymphoma in which an iris biopsy helped confirm the diagnosis.
Case Reports CASE 1
A 51-year-old woman presented with a 4-week history of floaters. Visual acuity was 20/30 in the right eye and 20/40 in the left. Funduscopic examination revealed a bilateral vitritis, diffuse RPE changes, and macular thickening. A diagnostic vitrectomy at that time showed inflammatory cells with atypical lymphocytes, but it was inconclusive for lymphoma. Five months later, the patient was referred to the National Eye Institute for further evaluation. Her corrected visual acuity was 20/20 in each eye. Ocular tensions were within normal limits in both eyes. Anterior segment examination showed bilateral scat-
tered old stellate keratic precipitates, and no other abnormalities were noted. Funduscopic examination of the right eye was significant for the presence of 1⫹ vitreous haze and 3⫹ vitreous cells. The left eye showed 2⫹ vitreous cells with a dense vitreous skirt over 360⬚. There were diffuse RPE changes, subretinal white infiltrates, and punched-out lesions in the periphery (Fig. 1). Workup at this time with lumbar puncture and magnetic resonance imaging (MRI) was normal. Another vitreous biopsy confirmed the diagnosis of B-cell lymphoma. Reults of other investigations were normal, including bone marrow aspirates, body computed tomography, and a repeat MRI. Two months later, the patient underwent treatment with brain and eye radiation (3,600 rads). Repeat lumbar punctures disclosed atypical lymphocytes, but the diagnosis remained inconclusive. An Ommaya reservoir was placed and followed by four intrathecal treatments with cytarabine. During the next several months, the patient’s condition remained stable, but bilateral posterior subcapsular cataracts developed. She underwent cataract extraction in the right eye 2 years after her initial presentation. When her left eye was evaluated a year later for possible cataract extraction, she was noted to have recurrent vitritis and decreased visual acuity to 20/100. She underwent cataract extraction with implantation of a posterior chamber intraocular lens (IOL). An iris biopsy and anterior chamber aspirate were performed at that time. Her postoperative course was significant for the development of dense keratic precipitates (Fig. 2, left). Analysis of the aqueous humor showed malignant cells, and the iris specimen showed stromal infiltration with B-cell lymphoma (Fig. 2, right). The patient was treated with systemic and intravitreal chemotherapy to her left eye, including daunorubicin, methotrexate, and thiotepa.13 Unfortunately, the left eye developed neovascular glaucoma with persistent loss of vision. The eye was enucleated 2 years later. Histopathologic examination showed it to be free of malignancy, but it had changes caused by radiation retinopathy. Subsequent follow-up showed no recurrence of tumor in the right eye. At the patient’s last visit 6 years later at the National Eye Institute, her visual acuity was 20/20 with no evidence of tumor recurrence. CASE 2
A 51-year-old white man presented to his physician with decreased vision in the right eye and floaters. Intermediate uveitis was diagnosed; the patient underwent pars plana vitrectomy with a scleral buckle, and his vision improved. Two years later he experienced similar symptoms in his left eye. A pars
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
Fig. 1. Case 1. Fundus photograph of the left eye showing multiple areas of subretinal discoloration consistent with atrophy and pigment migration. Small foci of active tumor infiltrates (arrows) are also observed.
plana vitrectomy and scleral buckle were performed in this eye also. Although his visual acuity improved, it remained persistently lower than baseline. Shortly thereafter, he developed bilateral cataracts and underwent cataract extraction with posterior chamber IOL placement, followed by Nd-YAG capsulotomies. Although his condition remained stable, bilateral vitreous cells persisted. Five years later, the patient developed episodes of increased intraocular pressure in the right eye. These episodes appeared to correlate with the degree of inflammation, and they often responded to topical corticosteroid treatment.
521
One year later, the patient’s right eye showed an increase of cells with a small fibrin clot in the anterior chamber and significant endothelial keratic precipitates. A clinical diagnosis of chronic postoperative endophthalmitis was made. The patient underwent a pars plana vitrectomy and capsulotomy with intraocular antibiotic injection and a sulcus-sutured lens exchange. However, intraocular inflammation with cellular deposits on the IOL progressed in his right eye. On evaluation by a uveitis specialist, the patient had a visual acuity of 20/80 in the right eye and 20/50 in the left. He had 1⫹ cells in the anterior chamber of the right eye, granulomatous IOL deposits, and 1⫹ cell and flare in the vitreous. The left eye had a quiet anterior chamber. Funduscopic examination showed multiple subretinal white lesions in both eyes (Fig. 3). An MRI was performed, which showed an enhancing lesion at the left caudate nucleus, consistent with CNS lymphoma. The patient was referred to the National Eye Institute for further evaluation. On examination, his visual acuity was stable at 20/80 in the right eye and 20/50 in the left. External examination showed iris heterochromia (Fig. 4). Slit-lamp examination of the anterior segment showed 3⫹ cells with 2⫹ flare in his right eye, and 1⫹ cells and flare in his left eye. His right iris appeared thickened with engorged vessels and nodular areas of infiltration. Gonioscopic examination of his right eye showed engorged vessels at the iris root with creamy, diffuse infiltrative lesions in the peripheral iris (Fig. 5). Funduscopic examination of the right eye showed 3⫹ vitreous cells with 2⫹ haze. A few scattered subretinal lesions were present in the periphery, with dif-
Fig. 2. Case 1. Left: Slit-lamp examination showing many dense, large keratic precipitates. Right: Photomicrograph showing malignant cells with large pleomorphic nuclei, scanty cytoplasm, and prominent nucleoli surrounding the iris vessels (hematoxylin & eosin, ⫻400).
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Iris Pathology
Fig. 3. Case 2. Fundus photograph of the right eye showing diffuse vitreous haze with a small area of tumor invasion (arrow) and a large chorioretinal scar, possibly corresponding to an area of previous tumor infiltration.
fuse areas of RPE depigmentation. Examination of the left eye showed scattered punched-out lesions with diffuse RPE changes. The patient underwent a diagnostic vitrectomy with an iris biopsy shortly thereafter. The vitreous specimen showed cells consistent with the diagnosis of B-cell lymphoma. The iris specimen showed stromal infiltration with large B-cell lymphoma (Fig. 6). Systemic evaluation with a lumbar puncture confirmed involvement of the CNS. The patient underwent treatment with systemic chemotherapy and intrathecal enhancement. After six cycles of treatment, the patient demonstrated resolution of the iris infiltration with normalization of the iris in the right eye. Vitreous biopsy, however, continued to demonstrate intraocular involvement.
Both iris biopsy specimens were processed for routine histopathology, electron microscopy, and immunohistochemical staining. The portion for routine histopathology was fixed in 10% formaldehyde and embedded in glycol methacrylate; the portion for electron microscopy was fixed in glutaraldehyde. The portion for immunohistochemistry was embedded in OCT (Miles Scientific, Naperville, IL, USA), snap frozen, and serially sectioned. The sections for immunohistochemistry were stained with the avidinbiotin complex immunoperoxidase technique. Primary monoclonal antibodies included antihuman B cells (CD 19, CD 20), T cells (CD3, CD4, CD8), macrophage (CD68), and kappa and lambda light chain. The iris histopathology of case 1 showed isolated mononuclear cells with scanty basophilic cytoplasm, large convoluted nuclei, and prominent nucleoli in the stroma and the perivascular region (Fig. 2, right). These cells stained positively for CD19, CD20, and kappa light chain. The iris specimens of case 2 showed diffuse infiltration of the iris stroma by large atypical pleomorphic cells with prominent nucleoli (Fig. 6, top). Scattered degenerating cells and mononuclear inflammatory cells (T cells and macrophages) were present. The infiltrating tumor cells were strongly positive for the B-cell marker CD19, CD20, and the kappa light chain (Fig. 6, bottom). Anterior segment fluid on case 1 was submitted for cytokine analysis. The interleukin (IL) 6 level was 1,348 pg/ml, while the IL-10 level was 51,000 pg/ml, yielding a high IL-10 to IL-6 ratio of 38:1.
Discussion Non-Hodgkin’s lymphoma involves ocular tissues either as a primary tumor or as secondary metastasis from systemic disease. Table 1 summarizes 163 re-
Fig. 4. Case 2. External photographs showing heterochromia. Note the thickened iris with engorged vessels in the right eye. Left: Right eye. Right: Left eye.
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
Fig. 5. Case 2. Slit-lamp examination of the right eye showing nodular infiltrates in the peripheral iris and engorged vessels in the iris.
523
ported cases of primary intraocular lymphoma, including clinical and histopathologic findings. Table 2 summarizes the clinical findings of all the cases surveyed. Vitritis is the most common finding in these patients (66%), followed by anterior chamber involvement (43%) and subretinal infiltrates (41%). In many cases, anterior and posterior segment findings are not present simultaneously. Most often, posterior segment findings precede anterior segment involvement. However, anterior segment involvement presenting as iridocyclitis and glaucoma can precede detection of subretinal infiltrates.39,56 Histopathologic examination of the anterior chamber of eyes with primary intraocular lymphoma often demonstrates reactive and inflammatory cells. On rare occasions, abnormal lymphoid cells have been retrieved from the anterior chamber of some patients by fine-needle aspiration.10,53 Uveal infiltration by malignant cells in systemic large B-cell lymphoma has been documented in the literature.9,11,14,40,52 However, in primary intraocular
Fig. 6. Case 2. Photomicrographs showing diffuse B-lymphoma cells infiltrating the iris stroma. Top: Malignant cells replace the normal iris stromal cells (hematoxylin & eosin, ⫻200). Bottom: Malignant cells stain positively for B-cell marker, CD19 (avidin-biotin complex immunoperoxidase, ⫻200).
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lymphoma, uveal involvement, particularly of the iris or ciliary body, is extremely rare and has been confirmed by histopathology in only a handful of patients. This could be due to the intrinsic nature of this tumor with its lack of uveal involvement. On the other hand, uveal infiltration may occur more often than we suspect, and the scarcity of histopathologic reports in the literature makes it a rare phenomenon. Of the papers reviewed in Table 1, for example, only 19 reported cases included histopathologic findings. Table 3 summarizes the cases of primary intraocular large B-cell lymphoma involving the iris reported in the literature. Of the 163 cases surveyed, only five include involvement of the iris, one of which was suspected by ultrasound. In only two of the five cases was iris involvement confirmed by histopathologic observation of malignant cells. In all of these cases, histopathology was performed post mortem or after enucleation.38,39,56 Patients with iris involvement from a primary intraocular large B-cell lymphoma share certain common characteristics that may shed light on the mechanism of uveal infiltration (Table 3). First, three of the patients (including case 1 in this report) were phakic with an intact iris-lens diaphragm at the time of iris involvement. Two patients—case 2 in this report and the one presented by Raju and Green39—were pseudophakic. This suggests that a disrupted iris-lens diaphragm is not necessary to allow anterior segment infiltration and seeding by malignant cells. Secondary glaucoma was also a common clinical finding in these patients. Glaucoma in these cases has been reported to occur by direct tumor infiltration of the angle39,56 or secondary to angle neovascularization in the absence of tumor cells.52 In case 2 of this report, dense tumor infiltration of the angle was visible on clinical examination, but no rubeosis or angle neovascularization was observed. Although intraocular pressure was better controlled once this infiltration had resolved with systemic chemotherapy,
diffuse destruction of the angle had occurred, requiring continued medical management. The mechanisms allowing uveal invasion by malignant cells remain a mystery. As mentioned earlier, histopathologic reports of primary intraocular lymphoma usually show predominantly inflammatory rather than malignant cells in the choroid. Although anatomic disruption of the iris-lens barrier between the posterior and anterior segments could facilitate migration of vitreal malignant cells into the anterior uvea, this does not seem to be the case, given the large proportion of phakic patients with this finding. It is more likely that malignant cells, after their invasion into the anterior chamber, can seed the iris stroma. Hematogenous spread, unlike systemic lymphoma, is very unlikely, given the low incidence of systemic metastasis through hematogenous spread to other organs in this form of the disease. However, it is interesting to note that histopathologic examination of two specimens, case 1 in our report and that presented by Vogel and colleagues,56 demonstrates a perivascular distribution of malignant cells in the iris. Finally, one must consider the possibility that these may be aggressive, long-standing tumors that broke through Bruch’s membrane and invaded the choroid, gaining access and slowly spreading into the anterior uveal structures. This possible mechanism is suggested by the presence of cells in the choroid of two patients with iris involvement reported in the literature.39,56 The patients presented here represent the first reported cases in which an iris biopsy was performed to make the diagnosis. The diagnosis of primary intraocular lymphoma by vitreous, chorioretinal, or subretinal biopsy has been previously described.4,5,8, 17,21,24,29,45,46,59 Identification of lymphoma cells in the vitreous is considered the gold standard for the diagnosis of this disease.6,12,15,59 Cells have also been identified in the anterior chamber aqueous.52 Retrieval of cells from intraocular fluids, however, can often be inconclusive, given the fragility of the cells shed
TABLE 3
Documented Case Reports of Primary Intraocular Lymphoma With Iris and/or Ciliary Body Infiltration First Author 56
Vogel Raju39 Corriveau10 Siegal47
AC CNS IR/SR Perivascular Secondary Cells/ Involvement Vitritis Infiltrates Infiltrates Glaucoma Pseudophakia Rubeosis KPs ON 2 1 1
2 1* 1 1
2 (1*)
1*
2 1
1 1
?
2 1* 1 1
Iris
CB
2 (1*) 1* 1† 1
2 (1*) 1* 1† 0
CNS ⫽ central nervous system; IR/SR ⫽ intraretinal/subretinal; AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; ON ⫽ optic nerve; CB ⫽ ciliary body. * Confirmed by histopathology. † Suspected clinically and by ultrasonography.
525
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
into the vitreous. Often a mixture of reactive lymphocytic infiltrate and necrotic tumor cells in the vitreous is found. Tissue diagnosis is then necessary, requiring an invasive chorioretinal, retinal, or subretinal biopsy. The presence of tumor cells in anterior uveal structures makes the diagnosis of primary intraocular lymphoma through less invasive measures a possibility. In patients with anterior segment involvement, even in the absence of an obvious iris mass, a less invasive and more benign iris biopsy and/ or anterior chamber tap can be considered as the first step toward establishing a diagnosis. It is important to note that, in case 1 of this report, there was no overt clinical evidence of iris or angle tumor infiltration. An iris biopsy, therefore, may provide valuable information even in patients with little clinical evidence of tumor invasion, and need not be restricted to patients with obvious iris nodules or thickening. Cytokine analysis of anterior segment fluid may also help to make a suspected diagnosis. The analysis of vitreous fluid for cytokines IL-6 and IL-10 and the correlation of these cytokines to active disease has been previously described.60 The presence of a higher IL-10 to IL-6 ratio has been correlated with the diagnosis of large B-cell lymphoma in both vitreous and cerebrospinal fluid. Case 1 in this report represents the first patient in whom such an analysis has been performed on aqueous fluid. The discovery of significant levels of these cytokines in the anterior chamber also raises the possibility of using less invasive procedures for the purpose of diagnosis as well. In summary, although primary intraocular large B-cell lymphoma is considered mostly a disease of the posterior segment, enough histopathologic evidence exists to suggest that invasion of the anterior segment structures by malignant cells may occur. Retrieval of malignant cells from the anterior chamber fluid and anterior chamber structures, such as the iris, combined with analysis of cytokine levels in the aqueous humor, can facilitate the diagnosis of this disease by avoiding more invasive posterior segment procedures.
Method of Literature Search The search engines PubMed and GratefulMed were used to perform the literature search on the database MEDLINE of the National Library of Medicine from the year 1966 to the present. Earlier sources were obtained by cross-referencing. Search words used included lymphoma, ocular, intraocular, and reticulum cell sarcoma. All articles and textbook references were retrieved, thoroughly reviewed, and quoted. Only articles available in the English language with detailed descriptions of the cases presented were included in this review.
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46.
47. 48. 49. 50.
51. 52. 53. 54. 55. 56. 57. 58. 59. 60.
of the eyes and brain. Diagnosis by transvitreal retinochoroidal biopsy. Ophthalmologica 195:135–40, 1987 Shen DF, Zhuang Z, LeHoang P, et al: Utility of microdissection and polymerase chain reaction for the detection of immunoglobulin gene rearrangement and translocation in primary intraocular lymphoma. Ophthalmology 105:1664–9, 1998 Siegel MJ, Dalton J, Friedman AH, et al: Ten-year experience with primary ocular reticulum cell sarcoma (large cell nonHodgkins lymphoma). Br J Ophthalmol 73:342–6, 1989 Simon JW, Friedman AH: Ocular reticulum cell sarcoma. Br J Ophthalmol 64:793–9, 1980 Sloas HA, Starling J, Harper DG, Cupples HP: Update of ocular reticulum cell sarcoma. Arch Ophthalmol 99:1048–52, 1981 Soussain C, Merle-Beral H, Reux I, et al: A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases. Leuk Lymphoma 23:339–45, 1996 Strauchen JA, Dalton J, Friedman AH: Chemotherapy in the management of intraocular lymphoma. Cancer 63:1918–21, 1989 Sullivan SF, Dallow RI: Intraocular reticulum cell sarcoma: its dramatic response to systemic chemotherapy and its angiogenic potential. Ann Ophthalmol 9:401–6, 1977 Trudeau M, Shepherd FA, Blackstein ME, et al: Intraocular lymphoma: report of three cases and review of the literature. Am J Clin Oncol 11:126–30, 1988 Ursea R, Heinemann MH, Silverman RH, et al: Ophthalmic, ultrasonographic findings in primary central nervous system lymphoma with ocular involvement. Retina 17:118–23, 1997 Valluri S, Moorthy RS, Khan A, Rao NA: Combination treatment of intraocular lymphoma. Retina 15:125–9, 1995 Vogel MH, Font RL, Zimmerman LE, Levine RA: Reticulum cell sarcoma of the retina and uvea: report of six cases and review of the literature. Am J Ophthalmol 66:205–15, 1968 Wagoner MD, Gonder JR, Albert DM, Canny CL: Ocular pathology for clinicians, 3: intraocular reticulum cell sarcoma. Ophthalmology 87:724–7, 1980 Walsh FB, Shewmake BJ: An unusual case of reticulum cell sarcoma. Am J Ophthalmol 74:741–3, 1972 Whitcup SM, de Smet MD, Rubin BI, et al: Intraocular lymphoma: clinical and histopathologic diagnosis. Ophthalmology 100:1399–406, 1993 Whitcup SM, Stark-Vancs V, Wittes RE, et al: Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 115:1157–60, 1997
The authors have no proprietary or commercial interest in any product or concept discussed in this article. Reprint address: Gisela Velez, MD, Bldg. 10, Rm. 10S219, NIH/ NEI, 10 Center Drive, Bethesda, MD 20892-1857.
CLINICAL PATHOLOGIC REVIEW DAVID APPLE AND MILTON BONIUK, EDITORS
Iris Involvement in Primary Intraocular Lymphoma: Report of Two Cases and Review of the Literature Gisela Velez, MD, MPH,1 Marc D. de Smet, MD,1,2 Scott M. Whitcup, MD,1 Michael Robinson, MD,1 Robert B. Nussenblatt, MD,1 and Chi-Chao Chan, MD1 1 2
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA, and Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Abstract. Non-Hodgkin’s lymphoma involves ocular tissues either as a primary tumor or as secondary metastasis from systemic disease. Diagnosis is based on the identification of malignant cells in the eye by biopsy. Although primary intraocular lymphoma cells have been identified in the optic nerve, ciliary body, and iris of a small number of patients by histopathology, these sites of infiltration have rarely been observed on clinical examination. We studied clinical and histopathological findings of two patients with iris infiltration by primary intraocular lymphoma and reviewed the findings of 163 cases reported in the literature. (Surv Ophthalmol 44:518–526, 2000. © 2000 by Elsevier Science Inc. All rights reserved.) Key words. iris • large B-cell lymphoma • lymphoma • non-Hodgkin’s lymphoma
Primary intraocular lymphoma, previously known as reticulum cell sarcoma, is thought to have been first reported by Cooper and Ricker in 1951.9 The disease occurs mostly in middle-aged and older adults, although patients as young as 15 years have been reported.36,38 Two clinically distinct forms of non-Hodgkin’s lymphoma can affect the eye. NonHodgkin’s lymphoma of the central nervous system (NHL-CNS) which includes primary intraocular lymphoma (PIOL), arises from the brain, spinal cord, leptomeninges, or eye.59 Systemic spread outside the CNS rarely occurs; it is reported in fewer than 10% of autopsies.19,32 Systemic non-Hodgkin’s lymphoma, unlike NHL-CNS, can metastasize to the eye through the choroidal circulation. This is suspected to be the situation in the case reported by Cooper and Ricker.9 Patients with non-Hodgkin’s lymphoma of the central nervous system often present with ocular dis-
ease before the development of neurologic involvement. The most common ocular symptoms include blurred vision and floaters; redness and pain are rare. Although the visual acuity may be decreased, it is usually better than would be expected from clinical examination. Table 1 summarizes the clinical findings of 163 cases of NHL-CNS of the eye reported in the literature. Vitritis was the most common finding, present in 66% of patients (Table 2). Anterior chamber cells were found in 43%, and cream-colored subretinal yellow infiltrates were reported in 41%. Diagnosis of NHL-CNS or primary intraocular lymphoma is based on the identification of malignant cells in the eye by vitreous biopsy or biopsy of other ocular tissues, such as a chorioretinal biopsy.59 Typical lymphoma cells are large with scanty basophilic cytoplasm, hypersegmented nuclei, and multiple nucleoli. Vitreous biopsy, however, usually contains a small number 518
© 2000 by Elsevier Science Inc. All rights reserved.
0039-6257/00/$–see front matter PII S0039-6257(00)00118-1
519
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA TABLE 1
Case Reports of Primary Intraocular Lymphoma With Associated Clinical and Histopathologic Findings First Author 56
Vogel Neault33 Appen2 Barr3 Klingele23 Minckler31 Kim20 Parver34 Rosenbaum44 Simon48 Wagoner57 Michelson30 Sloas49 Raju39 Qualman38 Gass18 Kline22 Purvin37 Rockwood43 Lang25 Corriveau10 Kirmani21 Scherfig45 Char7 Kuming24 Trudeau53 Siegal47 de Smet12 Strauchen51 Lopez26 Ridley41 Allinson1 Peterson36 Matsuo27 Pavan35 Valluri55 Soussain50 Ciulla8 Fishburne16 Ursea54 Shen46 Matsuo28 Buggage5 Rivero42 Total
No. of IR/SR Perivascular Posterior Patients Vitritis Infiltrates Infiltrates AC Cells/KPs Synechiae 6 7 1 3 7 1 1 1 1 3 1 1 1 1 5 3 1 1 3 1 1 1 1 9 1 2 14 1 6 1 5 1 24 1 1 3 8 1 4 13 3 10 1 2 163
4 7 1 3 7 1* 1 1* 1 3 1 1 1 1* 1* 2
6* 1
3*
2 6 1 1* 2 1*
6 3 1 1 7 1*
ON
Iris
Posterior and Anterior
1* 1
2* 3 1 1 7 1
2* 1*
1* 1*
CB
1* 1 1
1 1
1* 1
1 1* 5* 3
1*
5*
1* 1*
3* 1 1 1
3 1* 1 1 1 9 1 1 14 1 6 1 5 1 21 1 1 3 8 1 4 10‡ 2* 7 1 2 107
3 1* 1 1 1 6 1 2 7 1 2 1 4
1 1 1 5
1
1‡
1
1‡
? 5
1 3 1 1
1*
1 1 1
1 3 1
1 1 1 8 1 3 3‡ 3* 7 1 2* 66
1†
3 1 6 1
3 1 6
1† 1 1
1 2
1 6 1
1 ? 1 4‡ 2
1 1 19
9 1 1 70
1‡
2 (1†) 5
20
5
1 1 37
7
IR/SR ⫽ intraretinal and subretinal; AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; ON ⫽ optic nerve; CB ⫽ ciliary body. * Confirmed by histopathology. † No history of surgical intervention. ‡ Suspected clinically and by ultrasonography.
of these atypical cells. Most of the biopsy material is reactive lymphocytes, histiocytes, debris, and fibrinous material, particularly in the early stage of the malignancy. Furthermore, the malignant cells are extremely fragile. Cell viability can be increased by adding tissue culture medium (RPMI-1640, Rosewell Park Memorial Institute, Mediatech, Inc., Herndon, VA, USA) en-
riched with 10% fetal calf serum to the initial undiluted vitreous specimen.59 In addition, the person handling the specimen must take care to minimize cell lysis. Immunohistochemistry performed on suspicious cells aids the diagnosis, because the majority of primary intraocular lymphomas are of B-cell lineage.
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TABLE 2
Clinical Characteristics of Documented Case Reports With Primary Intraocular Lymphoma Characteristic Vitritis AC cells/KPs IR/SR Infiltrates Posterior and Anterior ON Perivasculitis Iris CB
No.
%
107 70 66 37 18 19 5 7
66 43 41 23 11 12 3 4
AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; IR/ SR ⫽ intraretinal and subretinal; ON ⫽ optic nerve; CB ⫽ ciliary body.
The finding of B-cell markers with a kappa or lambda light chain monoclonal response confirms the diagnosis. In patients who do not demonstrate a dense vitritis but do have the subretinal infiltrates consistent with the disease, a chorioretinal biopsy can be taken, or the subretinal space can be flushed with saline and the aspirate sent for pathologic examination.4,21,46 A typical chorioretinal biopsy will show malignant cells between Bruch’s membrane and the retinal pigment epithelium (RPE). While reactive cells can be seen in the retina, their numbers are limited. In the choroid, this reaction is much more significant.5,20,23,26,34 Though primary intraocular lymphoma cells have been identified in the optic nerve, ciliary body, and iris of a small number of patients by histopathology, these sites of infiltration have rarely been observed on clinical examination. Iris and ciliary body infiltrations, in particular, have been confirmed only after enucleation of eyes or on postmortem examination.3,39,56,58 Infiltration of iris and ciliary body by tumor originating in the eye or brain has, therefore, rarely been documented. We present the clinical and histopathologic findings of two patients with iris infiltration by primary intraocular lymphoma in which an iris biopsy helped confirm the diagnosis.
Case Reports CASE 1
A 51-year-old woman presented with a 4-week history of floaters. Visual acuity was 20/30 in the right eye and 20/40 in the left. Funduscopic examination revealed a bilateral vitritis, diffuse RPE changes, and macular thickening. A diagnostic vitrectomy at that time showed inflammatory cells with atypical lymphocytes, but it was inconclusive for lymphoma. Five months later, the patient was referred to the National Eye Institute for further evaluation. Her corrected visual acuity was 20/20 in each eye. Ocular tensions were within normal limits in both eyes. Anterior segment examination showed bilateral scat-
tered old stellate keratic precipitates, and no other abnormalities were noted. Funduscopic examination of the right eye was significant for the presence of 1⫹ vitreous haze and 3⫹ vitreous cells. The left eye showed 2⫹ vitreous cells with a dense vitreous skirt over 360⬚. There were diffuse RPE changes, subretinal white infiltrates, and punched-out lesions in the periphery (Fig. 1). Workup at this time with lumbar puncture and magnetic resonance imaging (MRI) was normal. Another vitreous biopsy confirmed the diagnosis of B-cell lymphoma. Reults of other investigations were normal, including bone marrow aspirates, body computed tomography, and a repeat MRI. Two months later, the patient underwent treatment with brain and eye radiation (3,600 rads). Repeat lumbar punctures disclosed atypical lymphocytes, but the diagnosis remained inconclusive. An Ommaya reservoir was placed and followed by four intrathecal treatments with cytarabine. During the next several months, the patient’s condition remained stable, but bilateral posterior subcapsular cataracts developed. She underwent cataract extraction in the right eye 2 years after her initial presentation. When her left eye was evaluated a year later for possible cataract extraction, she was noted to have recurrent vitritis and decreased visual acuity to 20/100. She underwent cataract extraction with implantation of a posterior chamber intraocular lens (IOL). An iris biopsy and anterior chamber aspirate were performed at that time. Her postoperative course was significant for the development of dense keratic precipitates (Fig. 2, left). Analysis of the aqueous humor showed malignant cells, and the iris specimen showed stromal infiltration with B-cell lymphoma (Fig. 2, right). The patient was treated with systemic and intravitreal chemotherapy to her left eye, including daunorubicin, methotrexate, and thiotepa.13 Unfortunately, the left eye developed neovascular glaucoma with persistent loss of vision. The eye was enucleated 2 years later. Histopathologic examination showed it to be free of malignancy, but it had changes caused by radiation retinopathy. Subsequent follow-up showed no recurrence of tumor in the right eye. At the patient’s last visit 6 years later at the National Eye Institute, her visual acuity was 20/20 with no evidence of tumor recurrence. CASE 2
A 51-year-old white man presented to his physician with decreased vision in the right eye and floaters. Intermediate uveitis was diagnosed; the patient underwent pars plana vitrectomy with a scleral buckle, and his vision improved. Two years later he experienced similar symptoms in his left eye. A pars
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
Fig. 1. Case 1. Fundus photograph of the left eye showing multiple areas of subretinal discoloration consistent with atrophy and pigment migration. Small foci of active tumor infiltrates (arrows) are also observed.
plana vitrectomy and scleral buckle were performed in this eye also. Although his visual acuity improved, it remained persistently lower than baseline. Shortly thereafter, he developed bilateral cataracts and underwent cataract extraction with posterior chamber IOL placement, followed by Nd-YAG capsulotomies. Although his condition remained stable, bilateral vitreous cells persisted. Five years later, the patient developed episodes of increased intraocular pressure in the right eye. These episodes appeared to correlate with the degree of inflammation, and they often responded to topical corticosteroid treatment.
521
One year later, the patient’s right eye showed an increase of cells with a small fibrin clot in the anterior chamber and significant endothelial keratic precipitates. A clinical diagnosis of chronic postoperative endophthalmitis was made. The patient underwent a pars plana vitrectomy and capsulotomy with intraocular antibiotic injection and a sulcus-sutured lens exchange. However, intraocular inflammation with cellular deposits on the IOL progressed in his right eye. On evaluation by a uveitis specialist, the patient had a visual acuity of 20/80 in the right eye and 20/50 in the left. He had 1⫹ cells in the anterior chamber of the right eye, granulomatous IOL deposits, and 1⫹ cell and flare in the vitreous. The left eye had a quiet anterior chamber. Funduscopic examination showed multiple subretinal white lesions in both eyes (Fig. 3). An MRI was performed, which showed an enhancing lesion at the left caudate nucleus, consistent with CNS lymphoma. The patient was referred to the National Eye Institute for further evaluation. On examination, his visual acuity was stable at 20/80 in the right eye and 20/50 in the left. External examination showed iris heterochromia (Fig. 4). Slit-lamp examination of the anterior segment showed 3⫹ cells with 2⫹ flare in his right eye, and 1⫹ cells and flare in his left eye. His right iris appeared thickened with engorged vessels and nodular areas of infiltration. Gonioscopic examination of his right eye showed engorged vessels at the iris root with creamy, diffuse infiltrative lesions in the peripheral iris (Fig. 5). Funduscopic examination of the right eye showed 3⫹ vitreous cells with 2⫹ haze. A few scattered subretinal lesions were present in the periphery, with dif-
Fig. 2. Case 1. Left: Slit-lamp examination showing many dense, large keratic precipitates. Right: Photomicrograph showing malignant cells with large pleomorphic nuclei, scanty cytoplasm, and prominent nucleoli surrounding the iris vessels (hematoxylin & eosin, ⫻400).
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Iris Pathology
Fig. 3. Case 2. Fundus photograph of the right eye showing diffuse vitreous haze with a small area of tumor invasion (arrow) and a large chorioretinal scar, possibly corresponding to an area of previous tumor infiltration.
fuse areas of RPE depigmentation. Examination of the left eye showed scattered punched-out lesions with diffuse RPE changes. The patient underwent a diagnostic vitrectomy with an iris biopsy shortly thereafter. The vitreous specimen showed cells consistent with the diagnosis of B-cell lymphoma. The iris specimen showed stromal infiltration with large B-cell lymphoma (Fig. 6). Systemic evaluation with a lumbar puncture confirmed involvement of the CNS. The patient underwent treatment with systemic chemotherapy and intrathecal enhancement. After six cycles of treatment, the patient demonstrated resolution of the iris infiltration with normalization of the iris in the right eye. Vitreous biopsy, however, continued to demonstrate intraocular involvement.
Both iris biopsy specimens were processed for routine histopathology, electron microscopy, and immunohistochemical staining. The portion for routine histopathology was fixed in 10% formaldehyde and embedded in glycol methacrylate; the portion for electron microscopy was fixed in glutaraldehyde. The portion for immunohistochemistry was embedded in OCT (Miles Scientific, Naperville, IL, USA), snap frozen, and serially sectioned. The sections for immunohistochemistry were stained with the avidinbiotin complex immunoperoxidase technique. Primary monoclonal antibodies included antihuman B cells (CD 19, CD 20), T cells (CD3, CD4, CD8), macrophage (CD68), and kappa and lambda light chain. The iris histopathology of case 1 showed isolated mononuclear cells with scanty basophilic cytoplasm, large convoluted nuclei, and prominent nucleoli in the stroma and the perivascular region (Fig. 2, right). These cells stained positively for CD19, CD20, and kappa light chain. The iris specimens of case 2 showed diffuse infiltration of the iris stroma by large atypical pleomorphic cells with prominent nucleoli (Fig. 6, top). Scattered degenerating cells and mononuclear inflammatory cells (T cells and macrophages) were present. The infiltrating tumor cells were strongly positive for the B-cell marker CD19, CD20, and the kappa light chain (Fig. 6, bottom). Anterior segment fluid on case 1 was submitted for cytokine analysis. The interleukin (IL) 6 level was 1,348 pg/ml, while the IL-10 level was 51,000 pg/ml, yielding a high IL-10 to IL-6 ratio of 38:1.
Discussion Non-Hodgkin’s lymphoma involves ocular tissues either as a primary tumor or as secondary metastasis from systemic disease. Table 1 summarizes 163 re-
Fig. 4. Case 2. External photographs showing heterochromia. Note the thickened iris with engorged vessels in the right eye. Left: Right eye. Right: Left eye.
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
Fig. 5. Case 2. Slit-lamp examination of the right eye showing nodular infiltrates in the peripheral iris and engorged vessels in the iris.
523
ported cases of primary intraocular lymphoma, including clinical and histopathologic findings. Table 2 summarizes the clinical findings of all the cases surveyed. Vitritis is the most common finding in these patients (66%), followed by anterior chamber involvement (43%) and subretinal infiltrates (41%). In many cases, anterior and posterior segment findings are not present simultaneously. Most often, posterior segment findings precede anterior segment involvement. However, anterior segment involvement presenting as iridocyclitis and glaucoma can precede detection of subretinal infiltrates.39,56 Histopathologic examination of the anterior chamber of eyes with primary intraocular lymphoma often demonstrates reactive and inflammatory cells. On rare occasions, abnormal lymphoid cells have been retrieved from the anterior chamber of some patients by fine-needle aspiration.10,53 Uveal infiltration by malignant cells in systemic large B-cell lymphoma has been documented in the literature.9,11,14,40,52 However, in primary intraocular
Fig. 6. Case 2. Photomicrographs showing diffuse B-lymphoma cells infiltrating the iris stroma. Top: Malignant cells replace the normal iris stromal cells (hematoxylin & eosin, ⫻200). Bottom: Malignant cells stain positively for B-cell marker, CD19 (avidin-biotin complex immunoperoxidase, ⫻200).
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lymphoma, uveal involvement, particularly of the iris or ciliary body, is extremely rare and has been confirmed by histopathology in only a handful of patients. This could be due to the intrinsic nature of this tumor with its lack of uveal involvement. On the other hand, uveal infiltration may occur more often than we suspect, and the scarcity of histopathologic reports in the literature makes it a rare phenomenon. Of the papers reviewed in Table 1, for example, only 19 reported cases included histopathologic findings. Table 3 summarizes the cases of primary intraocular large B-cell lymphoma involving the iris reported in the literature. Of the 163 cases surveyed, only five include involvement of the iris, one of which was suspected by ultrasound. In only two of the five cases was iris involvement confirmed by histopathologic observation of malignant cells. In all of these cases, histopathology was performed post mortem or after enucleation.38,39,56 Patients with iris involvement from a primary intraocular large B-cell lymphoma share certain common characteristics that may shed light on the mechanism of uveal infiltration (Table 3). First, three of the patients (including case 1 in this report) were phakic with an intact iris-lens diaphragm at the time of iris involvement. Two patients—case 2 in this report and the one presented by Raju and Green39—were pseudophakic. This suggests that a disrupted iris-lens diaphragm is not necessary to allow anterior segment infiltration and seeding by malignant cells. Secondary glaucoma was also a common clinical finding in these patients. Glaucoma in these cases has been reported to occur by direct tumor infiltration of the angle39,56 or secondary to angle neovascularization in the absence of tumor cells.52 In case 2 of this report, dense tumor infiltration of the angle was visible on clinical examination, but no rubeosis or angle neovascularization was observed. Although intraocular pressure was better controlled once this infiltration had resolved with systemic chemotherapy,
diffuse destruction of the angle had occurred, requiring continued medical management. The mechanisms allowing uveal invasion by malignant cells remain a mystery. As mentioned earlier, histopathologic reports of primary intraocular lymphoma usually show predominantly inflammatory rather than malignant cells in the choroid. Although anatomic disruption of the iris-lens barrier between the posterior and anterior segments could facilitate migration of vitreal malignant cells into the anterior uvea, this does not seem to be the case, given the large proportion of phakic patients with this finding. It is more likely that malignant cells, after their invasion into the anterior chamber, can seed the iris stroma. Hematogenous spread, unlike systemic lymphoma, is very unlikely, given the low incidence of systemic metastasis through hematogenous spread to other organs in this form of the disease. However, it is interesting to note that histopathologic examination of two specimens, case 1 in our report and that presented by Vogel and colleagues,56 demonstrates a perivascular distribution of malignant cells in the iris. Finally, one must consider the possibility that these may be aggressive, long-standing tumors that broke through Bruch’s membrane and invaded the choroid, gaining access and slowly spreading into the anterior uveal structures. This possible mechanism is suggested by the presence of cells in the choroid of two patients with iris involvement reported in the literature.39,56 The patients presented here represent the first reported cases in which an iris biopsy was performed to make the diagnosis. The diagnosis of primary intraocular lymphoma by vitreous, chorioretinal, or subretinal biopsy has been previously described.4,5,8, 17,21,24,29,45,46,59 Identification of lymphoma cells in the vitreous is considered the gold standard for the diagnosis of this disease.6,12,15,59 Cells have also been identified in the anterior chamber aqueous.52 Retrieval of cells from intraocular fluids, however, can often be inconclusive, given the fragility of the cells shed
TABLE 3
Documented Case Reports of Primary Intraocular Lymphoma With Iris and/or Ciliary Body Infiltration First Author 56
Vogel Raju39 Corriveau10 Siegal47
AC CNS IR/SR Perivascular Secondary Cells/ Involvement Vitritis Infiltrates Infiltrates Glaucoma Pseudophakia Rubeosis KPs ON 2 1 1
2 1* 1 1
2 (1*)
1*
2 1
1 1
?
2 1* 1 1
Iris
CB
2 (1*) 1* 1† 1
2 (1*) 1* 1† 0
CNS ⫽ central nervous system; IR/SR ⫽ intraretinal/subretinal; AC ⫽ anterior chamber; KPs ⫽ keratic precipitates; ON ⫽ optic nerve; CB ⫽ ciliary body. * Confirmed by histopathology. † Suspected clinically and by ultrasonography.
525
IRIS INVOLVEMENT IN PRIMARY INTRAOCULAR LYMPHOMA
into the vitreous. Often a mixture of reactive lymphocytic infiltrate and necrotic tumor cells in the vitreous is found. Tissue diagnosis is then necessary, requiring an invasive chorioretinal, retinal, or subretinal biopsy. The presence of tumor cells in anterior uveal structures makes the diagnosis of primary intraocular lymphoma through less invasive measures a possibility. In patients with anterior segment involvement, even in the absence of an obvious iris mass, a less invasive and more benign iris biopsy and/ or anterior chamber tap can be considered as the first step toward establishing a diagnosis. It is important to note that, in case 1 of this report, there was no overt clinical evidence of iris or angle tumor infiltration. An iris biopsy, therefore, may provide valuable information even in patients with little clinical evidence of tumor invasion, and need not be restricted to patients with obvious iris nodules or thickening. Cytokine analysis of anterior segment fluid may also help to make a suspected diagnosis. The analysis of vitreous fluid for cytokines IL-6 and IL-10 and the correlation of these cytokines to active disease has been previously described.60 The presence of a higher IL-10 to IL-6 ratio has been correlated with the diagnosis of large B-cell lymphoma in both vitreous and cerebrospinal fluid. Case 1 in this report represents the first patient in whom such an analysis has been performed on aqueous fluid. The discovery of significant levels of these cytokines in the anterior chamber also raises the possibility of using less invasive procedures for the purpose of diagnosis as well. In summary, although primary intraocular large B-cell lymphoma is considered mostly a disease of the posterior segment, enough histopathologic evidence exists to suggest that invasion of the anterior segment structures by malignant cells may occur. Retrieval of malignant cells from the anterior chamber fluid and anterior chamber structures, such as the iris, combined with analysis of cytokine levels in the aqueous humor, can facilitate the diagnosis of this disease by avoiding more invasive posterior segment procedures.
Method of Literature Search The search engines PubMed and GratefulMed were used to perform the literature search on the database MEDLINE of the National Library of Medicine from the year 1966 to the present. Earlier sources were obtained by cross-referencing. Search words used included lymphoma, ocular, intraocular, and reticulum cell sarcoma. All articles and textbook references were retrieved, thoroughly reviewed, and quoted. Only articles available in the English language with detailed descriptions of the cases presented were included in this review.
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28. 29. 30.
31.
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The authors have no proprietary or commercial interest in any product or concept discussed in this article. Reprint address: Gisela Velez, MD, Bldg. 10, Rm. 10S219, NIH/ NEI, 10 Center Drive, Bethesda, MD 20892-1857.