Primary intraocular lymphomas are uncommon neoplasms that are usually of B-cell origin. They may be limited to the eye, but they can also be accompanied by an involvement of the central nervous system. A primary intraocular T-cell lymphoma is exceedingly rare, with a few cases documented by molecular analysis.1-3 Intraocular lymphomas typically affect elderly patients and can be unilateral (~20%) or bilateral (~80%). Two types are recognized: vitreoretinal and uveal. The vitreoretinal variety is not associated with systemic involvement, is accompanied by multiple solid detachments of the retinal pigment epithelium, does not usually involve the uveal tract, and may only involve the eye but sometimes affects the brain prior to or after the ocular manifestations. In contrast, uveal lymphoma of the eye is typically associated with a systemic lymphoma, and central nervous system involvement is rare. Risk factors for ocular lymphomas include organ transplantation, infection with human T-cell lymphotropic virus type 1, and acquired immunodeficiency syndrome.4
We present the case of a 57-year-old woman who underwent 3 diagnostic vitrectomies for a presumed diagnosis of panuveitis and who subsequently underwent enucleation of the left eye, whereby a primary intraocular B-cell lymphoma involving the choroid, vitreous, and retina was diagnosed. A large population of T cells was admixed with the neoplastic B-cell population. Molecular analyses showed a monoclonal B-cell population, which was correlated with the immunoglobulin κ light chain population and demonstrated a polyclonal T-cell population.
REPORT OF A CASE
A 57-year-old white woman was in her usual state of good health until December 1998, when she noticed floaters in her left eye while looking up into a clear blue sky. The patient's history included pernicious anemia (since 1997); hypercholesterolemia; basal cell carcinoma (2 excised in 1999, 1 from the leg and 1 from the forehead; 2 removed in 2000, 1 from the back and 1 from the left cheek); and cutaneous melanoma, Clark level III (right upper arm in April 1976; treated by wide excision with a right axillary lymph node dissection and immunotherapy protocol). She had multiple conventional roentgenograms during her evaluation for melanoma, but otherwise lacked known exposures to chemicals or radiation. The patient denied blood transfusions or other risk factors associated with human immunodeficiency virus.
Her vision deteriorated, and her eye physician told her that he felt that she had macular degeneration, although it was unusual to occur in 1 eye and at her age. In June 1999, she was examined by another ophthalmologist, who diagnosed pars planitis and prescribed prednisolone acetate eye drops for 4 to 6 weeks. Because the condition had not resolved by July 1999, she was referred to a vitreoretinal specialist. In August 1999, after magnetic resonance imaging of the brain and orbits did not disclose a mass lesion, a pars plans vitrectomy was performed on the left eye. The vitreous washings showed a T-cell lymphoproliferative process with an immunoprofile that was CD5 and CD19 negative and CD2, CDS, CD4, and CDS positive. The patient's vision decreased after the procedure. In October 1999, the patient had another vitrectomy that included cultures of the vitreous for microorganisms. This specimen showed a lymphoid proliferation composed primarily of small mature-appearing lymphocytes. A reactive process was favored, but in light of the clinical context, a low-grade lymphoma could not be excluded. She was treated with antibiotics for 1 month.
In January 2000, ophthalmoscopy of the left eye showed subretinal infiltrates (Figure 1, A). Another diagnostic vitrectomy was performed, together with an aspiration of material from a subretinal infiltrate, via a pars plana transvitreous approach. The vitreous aspiration contained degenerating cellular debris and rare viable large atypical cells (Figure 1, B). The patient was referred to another ophthalmologist when her vision worsened. Fluorescein angiography was performed and showed hypofluorescent spots in the posterior pole and some mottled fluorescence between the optic nerve and the macula, findings that correlated with the subretinal infiltrates observed by ophthalmoscopy.
The patient continued to be followed for a slowly progressive painless panuveitis with subretinal plaques strongly reminiscent of intraocular lymphoma. In December 2000 she presented to the Duke University Eye Center for another opinion, and the examination at that time revealed that the posterior pole of the left eye could not be clearly seen because of an opaque vitreous. A left afferent pupillary defect was present, and there was no light perception in that eye. The conjunctiva was injected, and the cornea had small and medium keratic precipitates interiorly. A flare (2 + ) and cells (3 + ) were noted in the anterior chamber. Diffuse iris neovascularization and posterior synechiae occluded almost 360
The blind left eye was enucleated in January 2001 to help establish the diagnosis and showed a mass lesion involving the vitreous cavity and with a mild thickening of the choroid (Figure 1, C). During the procedure, the optic nerve stump was noted to be thickened, and an orbital hydroxyapatite prosthesis was placed.
PATHOLOGIC FINDINGS
Light microscopy of the eye disclosed a uniform population of large atypical lymphoid cells involving the vitreous, retina, and choroid. The mass lesion that was observed grossly was composed of nodules of tumor cells, fibrin, hemorrhage, necrosis, and a focal peripheral nonfunnel-shaped type of retinal detachment. There was variable involvement and expansion of the choroid by the tumor, and in some foci there was an extension of the tumor through the choroid to the inner sciera (Figure 2, A). Tumor cells also infiltrated the smooth muscle of the ciliary body. Histologically, the large atypical cells were characterized by convoluted nuclear membranes and prominent nucleoli. The neoplastic cells were strongly immunoreactive to the B-cell marker CD20 (L26) in a membranous pattern (Figure 2, B) and were immunonegative to a highand low-molecular-weight cytokeratin cocktail (AE1/AE3 and CAM 5.2) and HMB-45. A large population of small T cells immunopositive for the T-cell marker CD3 was also identified, and they comprised approximately 50% of the lymphoid population (Figure 2, C). A 0.2-cm-thick fibrocellular layer at the junction of the choroid and retina was present, and the choroid was markedly thickened due to the tumor and its associated reactive T-cell infiltration. Other intraocular abnormalities included retinal degeneration with deficient retinal pigment epithelium. The left optic nerve stump contained neoplastic cells identical to those within the globe.
GENE REARRANGEMENT STUDIES
Immunoglobulin and T-cell receptor gene rearrangements were analyzed. Briefly, genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue. A total of 500 µg of DNA was added to the master mix of an IGH Gene Rearrangement/B-cell Clonality Assay Kit and a TCell Receptor Gene Rearrangement Assay Kit for immunoglobulin heavy and κ light-chain gene and T-cell receptor γ chain gene clonality studies, respectively (IVS Technologies, Carlsbad, Calif). The polymerase chain reaction products were analyzed in an ABI 310 capillary genetic analyzer (Applied Biosystems, Foster City, Calif) with a 47-cm × 500-µm capillary using Performance Optical Polymer 4. The gene products were analyzed with Genescan software (Applied Biosystems).
B-cell monoclonality of the immunoglobulin κ lightchain population was confirmed (Figure 3, A). A B-cell monoclonal heavy-chain population was not identified. T-cell receptor y gene rearrangement studies did not show evidence of T-cell gene rearrangement (Figure 3, B), and thus the T cells were confirmed to be reactive and not neoplastic.
PATIENT FOLLOW-UP
One-month postenucleation, magnetic resonance imaging showed an enlargement of the left optic nerve compared to the right, enhancement along the left optic nerve sheath, and intraconal enhancement along the temporal margin of the prosthesis. The changes were radiographically consistent with either a residual tumor or a post-operative inflammatory reaction. Cytologic examination findings of cerebrospinal fluid obtained from a lumbar puncture showed that it was within normal limits, and flow cytometric analysis showed a polyclonal population. The patient received radiation therapy to the left optic nerve and chiasm (14 treatments), which was followed by high-dose chemotherapy with Ara-C. Following this, she developed a febrile neutropenia, positive blood cultures for Staphylococcits coagitlase-negative bacteria, and a pruritic drug rash diagnosed as spongiotic dermatitis and alopecia. She subsequently developed a parietal brain lesion, which was found to be composed of an atypical lymphoid population suspected of being a lymphoma on biopsy. She was treated with low-dose whole-brain radiation and 4 cycles of high-dose methotrexate. At her most recent follow-up visit in December 2004, she was reported as "doing well."
COMMENT
The present case highlights the well-established observation that an ocular lymphoma can masquerade as uveitis. Despite 3 vitreous biopsies and 1 fine-needle subretinal aspiration, the diagnosis of an intraocular lymphoma was not established until after the enucleation. Vitreous biopsy is an effective method of establishing the diagnosis of an intraocular lymphoma in cases in which there is a requirement that it be distinguished from uveitis." However, an interpretation of vitreous cytology requires not only knowledge about the cellular composition of the vitreous in both health and disease, but also familiarity with ocular diseases that result in the manifestation of abnormalities in the vitreous. The presence of necrotic "ghost" cells in the background of a cytologic preparation rich in lymphocytes of which only a few might be malignant cells requires the interpretation by a cytopathologist with experience in ophthalmic pathology. Delayed diagnoses can be best avoided when pathologists and ophthalmologists are able to correlate the cytologic findings within the context of clinical information.
Large B-cell lymphomas containing a prominent component of reactive T-cell lymphocytes are usually referred to as T-cell-rich B-cell lymphomas when they constitute greater than 50% of the cellular population.10-14 It remains unclear whether T-cell-rich B-cell lymphomas are a distinct entity or a morphologic variation of a conventional large B-cell lymphoma.13 Reports of genotypic analysis using the Southern blot technique or polymerase chain reaction have not shown rearrangements of the T-cell receptor genes in cases of T-cell-rich B-cell lymphomas. Nevertheless, the role of the T-cell infiltrate in T-cell-rich B-cell lymphomas is uncertain, although a host reaction or a response to cytokines secreted by the neoplastic B cells has been proposed.15 Immunophenotyping of our case showed approximately an overall 50% population of reactive T cells, although in some areas, the T cells were markedly increased in number compared to the B cells, while in other areas, solid tumor foci were composed predominantly of neoplastic B cells. In our case, the finding of a marked T-cell proliferation led us to pursue genotypic analysis. The findings of a monoclonal immunoglobulin light chain population and the absence of a T-cell receptor gene rearrangement confirm that this was a B-cell-derived neoplasm and that the T-cell population was nonneoplastic. Although our case appears to fall under the diagnosis of T-cell-rich B-cell lymphomas, we anticipate that in such cases, an enucleation specimen presents only one point along a spectrum of T-cell infiltration, the temporal fluctuation of which is not entirely certain.
Also of note in this primary vitreoretinal lymphoma was the unusually prominent involvement of the choroid with an extension to the inner sciera and smooth muscle of the ciliary body.
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