Vitreoretinal lymphoma revealing Richter transformation

Abstract

Purpose

To report a rare case of Richter syndrome transformation presenting as diffuse large B-cell vitreoretinal lymphoma (DLBCL) in a patient with chronic lymphocytic leukemia (CLL).

Observations

A woman in her late fifties with 11q-mutated CLL in remission presented with bilateral, painless blurring of vision. The best-corrected visual acuity was 20/50 in the right eye and 20/80 in the left eye. Fundus examination revealed multiple hypopigmented yellowish subretinal lesions in both eyes. A presumed diagnosis of secondary vitreoretinal lymphoma/leukemic infiltration was made, and multiple intravitreal methotrexate injections were administered until complete regression of lesions and visual recovery. However, a year later, the left eye relapsed with a large placoid, yellowish subretinal infiltration. ^18F-FDG PET–CT scan revealed systemic lymphadenopathy. Subretinal and vitreous biopsy revealed CD20⁻and BCL2-positive large atypical lymphoid cells, confirming DLBCL, consistent with Richter transformation in the eye. Although lymph node and tonsillar biopsies showed no systemic involvement, the patient declined prophylactic high-dose methotrexate despite the elevated risk of systemic transformation.

Conclusion and importance

Bilateral vitreoretinal lymphoma presenting as the first manifestation of Richter transformation is exceedingly rare. Early ophthalmic recognition, biopsy, and systemic staging are essential for avoiding diagnostic delays.

Highlights

• •Vitreoretinal lymphoma may be the initial or sole manifestation of Richter transformation in patients with CLL, preceding systemic involvement.
• •Relapsing placoid subretinal infiltrates after initial response to intravitreal chemotherapy should raise suspicion for clonal transformation rather than recurrence of leukemic infiltration.
• •Early intraocular biopsy and comprehensive systemic staging are critical to establish the diagnosis and prevent delays in management.

1. Introduction

Richter syndrome describes the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma—most commonly diffuse large B-cell lymphoma (DLBCL)—with an incidence of 3–10% and poor prognosis (median survival 8–12 months despite treatment). 1, 2, 3 While ocular involvement is extremely rare as an initial presentation, extranodal sites are well known.⁴ Bilateral vitreoretinal lymphoma (VRL) presenting as the initial manifestation of Richter transformation is rare and represents an uncommon clinical presentation.

2. Case presentation

A woman in her late fifties presented to the outpatient department with fever and swelling of the neck and postauricular region. The patient was initially conservatively managed, and an extensive diagnostic workup was performed. Blood tests revealed severe anemia (hemoglobin 6.8 g/dL), marked leukocytosis (total leukocyte count 35 000/μL), and thrombocytosis (platelet count 4.21 × 10⁵/μL). A lymph node biopsy revealed reactive lymphoid hyperplasia. Whole-body computed tomography (CT) revealed supradiaphragmatic and infradiaphragmatic lymphadenopathy involving the mediastinal and abdominopelvic nodes, splenomegaly, and hepatomegaly. Whole-body positron emission tomography–computed tomography (PET–CT) revealed multiple hypermetabolic nodes.

Bone marrow examination revealed hypercellularity with diffuse lymphocyte infiltration. Flow cytometry of the peripheral blood revealed 72% atypical lymphoid cells expressing a B-cell immunophenotype. The neoplastic cells were positive for CD19, CD20, CD22, CD23 (63%), CD25 (27%), CD43 (42%), CD45 (52%), and CD200 (67%) and negative for CD3, CD5, CD10, CD11c, CD38, FMC7, and both κ and λ light chains. Taken together with the clinical context of lymphocytosis, lymphadenopathy, and splenomegaly, these findings confirmed the diagnosis of chronic lymphocytic leukemia (CLL), Rai stage V, with 11q22 mutation, confirmed with cytogenetic analysis.

The patient was started on six cycles of bendamustine (135 mg) in combination with rituximab (dose) and responded well to therapy, achieving remission.

One year later, the patient presented to the ophthalmology department with a 1-week history of painless blurring of vision in both eyes. On examination, the best-corrected visual acuity was 20/50 and 20/80 in the right eye and 20/80 in the left eye, respectively. Slit-lamp evaluation revealed bilateral anterior chamber cells with 1+ vitreous cells. Fundus examination revealed multiple discrete hypopigmented yellow subretinal lesions (Fig. 1A and B), which was more evident on autofluorescence and indocyanine green angiography (Fig. 1C–F). Magnetic resonance imaging of the brain revealed a benign lesion in the left cavernous sinus.

Fig. 1.

A, B: Fundus photographs reveal multiple discrete hypopigmented lesions over the posterior pole, with additional hyperpigmented lesions in the superonasal quadrant of the right eye and nasal quadrant in the left eye (arrows).

C, D: Autofluorescence images of both eyes show numerous tiny discrete hyperfluorescent lesions.

E, F: Indocyanine green angiography displays hypofluorescent lesions at the posterior pole in both eyes.

A presumptive diagnosis of leukemic infiltrative retinopathy was made, and the patient was treated with bilateral intravitreal methotrexate (0.4 mg/0.1 mL) every two weeks, for a total of two injections, which led to the resolution of the retinal lesions and vision recovery. However, one year later, she presented again with recurrent visual loss in the left eye. The best-corrected visual acuity was measured as 20/50 in the right eye and 20/80 in the left eye. Fundus examination revealed creamy-yellow subretinal infiltrates with associated hemorrhage and overlying subretinal fluid (Fig. 2A and B). Optical coherence tomography (OCT) revealed hyperreflective subretinal deposits (Fig. 2C), whereas PET–CT revealed metabolically active cervical, mediastinal, and abdominal lymphadenopathy. Considering these clinical and imaging findings, vitreoretinal lymphoma was strongly suspected, and a subretinal and vitreous biopsy was performed for definitive diagnosis.

Fig. 2.

A: Fundus photograph shows multiple hypopigmented yellowish subretinal lesions (arrows), consistent with vitreoretinal lymphoma.

B: Left eye exhibits a recurrent large yellowish area of subretinal infiltration, accompanied by hemorrhage and subretinal fluid.

C: Optical coherence tomography (OCT) reveals multiple hyperreflective subretinal deposits with associated subretinal fluid.

Cytological analysis revealed CD20⁻and BCL2-positive large atypical lymphoid cells, consistent with diffuse large B-cell lymphoma (DLBCL), confirming Richter transformation of CLL to DLBCL (Fig. 3A–D). The patient was referred to an oncologist for systemic evaluation. Axillary lymph node biopsy and tonsillectomy were performed, both of which were negative for lymphoma or leukemic infiltration. A repeat bone marrow biopsy showed normocellular marrow with adequate erythroid, myeloid, and megakaryocytic lineages. Flow cytometry detected 1% suspicious cells positive for CD19, CD20, and dim CD5 expression. Cytogenetic testing by FISH was negative for the 11q22 mutation, supporting an isolated ocular Richter transformation.

Fig. 3.

A. Photomicrograph of cell block preparation showing singly scattered intermediate to large atypical lymphoid cells (black arrowheads) (H&E, 4×).

B. Photomicrograph of cell block preparation showing singly scattered intermediate to large atypical lymphoid cells positive for CD20 (black arrowheads) (immunostain, 20×).

C. Photomicrograph of cell block preparation showing intermediate to large atypical lymphoid cells (black arrowheads) (H&E, 40×). The cells display round nuclei with conspicuous nucleoli and moderate cytoplasm, features suggestive of diffuse large B-cell lymphoma (DLBCL).

D. Photomicrograph of cell block preparation showing singly scattered intermediate to large atypical lymphoid cells diffusely expressing BCL2 (black arrowheads) (immunostain, 40×).

E. Fundus photograph of the left eye after three intravitreal methotrexate injections demonstrates resolution of lesions and hemorrhages, with surrounding retinal pigment epithelial atrophy.

The patient was started on intravitreal methotrexate (0.4 mg/0.1 mL), receiving a total of thirteen injections (eight in the left eye and five in the right eye). The therapeutic response was excellent, with improvement in visual acuity to 20/20 and complete regression of retinal lesions (Fig. 3E). In view of the high risk for systemic transformation, a tumor board recommended initiating prophylactic systemic high-dose methotrexate; however, the patient declined further treatment. The patient remains under close follow-up with a hematologist-oncologist, eight months after the last intravitreal injection, to monitor for systemic transformation.

3. Discussion

Richter syndrome represents the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). 1, 2, 3 While extranodal involvement in Richter transformation is well recognized, ocular involvement—particularly as an initial manifestation—is exceedingly rare.⁴ Bilateral vitreoretinal lymphoma presenting as the initial clinical evidence of Richter transformation is exceptionally rare and highlights the need for a high index of suspicion in patients with CLL who develop atypical intraocular infiltrates.

Three cases of Richter syndrome with ocular involvement have previously been reported; in two out of these three cases, enucleation (eye removal) was performed because transformation happened simultaneously in the eye and at systemic sites.5, 6, 7 In contrast, our patient showed intraocular infiltration as the first and only sign of transformation, confirmed by subretinal and vitreous biopsy, while systemic evaluations (including lymph node and tonsil biopsies) were negative. However, given the high risk of future systemic transformation, prophylactic systemic high-dose methotrexate was recommended, but the patient declined further treatment. From a diagnostic perspective, several conditions—such as infectious retinitis (viral, toxoplasmosis) and non-infectious uveitis—can resemble vitreoretinal lymphoma. However, the patient's existing history of CLL and biopsy-confirmed CD20/BCL2-positive atypical lymphoid cells led to the diagnosis of Richter transformation. This case demonstrates that ophthalmic signs may appear before any systemic evidence of transformation, prompting the need for immediate biopsy and staging workup.

4. Conclusion

Bilateral vitreoretinal lymphoma occurring as the initial manifestation of Richter transformation represents an exceptionally rare clinical presentation. This expands the known clinical spectrum of Richter syndrome and underscores the importance of vigilance when assessing unusual intraocular inflammation in CLL patients.

Informed consent

Written informed consent was obtained from the patient for publication of the case details after a thorough explanation of the study.

Financial Support

This work was supported by an unrestricted departmental grant from Hyderabad Eye Research Foundation, Hyderabad, India.

Statement of ethics

This study was approved by the Institutional Review board at L V Prasad Eye Institute.

Artificial intelligence statement

No artificial intelligence (AI) tools or generative AI technologies were used in the preparation, writing, analysis, or editing of this manuscript.

CRediT authorship contribution statement

Dibya Prabha: Data curation, Formal analysis, Writing – original draft. Vishal Raval: Conceptualization, Formal analysis, Validation, Writing – review & editing. Dilip Mishra: Formal analysis, Investigation, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.