A, Slitlamp examination reveals the presence of vitreous aggregates. B, From the vitreous aspiration biopsy sample, a cytospin preparation shows large atypical lymphocytes with a high ratio of nuclei to cytoplasm and scant cytoplasm (Diff-Quick stain, original magnification ×600). C, The cell block shows a cellular specimen composed mostly of large atypical lymphocytes with prominent nucleoli (hematoxylin-eosin, original magnification ×600). D, Staining of these cells was positive for CD20 (anti-CD20, original magnification ×600). E, The cervical lymph node biopsy specimen reveals large B-cell lymphoma (hematoxylin-eosin, original magnification ×600). F, Optical coherence tomography reveals subretinal and retinal infiltrates.
A, Fundus photograph shows vitreous haziness. B, Optical coherence tomography reveals irregularities at the retinal pigment epithelium layer. C, The vitreous aspiration biopsy sample shows a cellular specimen represented by large atypical lymphocytes with prominent nucleoli (hematoxylin-eosin, original magnification ×600). Inset highlights the prominent nucleoli (original magnification ×1000). D, Staining of the cells was positive for CD20 (anti-CD20, original magnification ×600).
Salomão DR, Pulido JS, Johnston PB, Canal-Fontcuberta I, Feldman AL. Vitreoretinal Presentation of Secondary Large B-Cell Lymphoma in Patients With Systemic Lymphoma. JAMA Ophthalmol. 2013;131(9):1151-1158. doi:10.1001/jamaophthalmol.2013.334
Intraocular lymphomas represent a diverse group of hematologic malignant neoplasms involving different tissues within the eye. Predominant involvement of the retina and vitreous without uveal infiltration in systemic lymphoma, mimicking a primary vitreoretinal lymphoma, is extremely rare. Our study emphasizes the importance of systemic evaluation in addition to central nervous system evaluation in all patients with newly diagnosed vitreoretinal lymphoma.
To determine the incidence of secondary intraocular lymphoma presenting as vitreoretinal infiltrates without central nervous system involvement, mimicking primary vitreoretinal lymphoma in patients with systemic lymphoma.
Retrospective review of all vitreous aspiration biopsy samples acquired because malignant neoplasm was suspected clinically that were obtained at our institution from January 1, 2000, through December 31, 2010. Review included patient clinical history, radiographic study findings, cytologic and/or histologic preparations, immunophenotypic study findings, treatment, and outcomes.
Mayo Clinic pathology database.
Fifty-five patients with vitreous specimens available for review.
Vitreous aspiration biopsy.
Main Outcome and Measure
Confirmation of the diagnosis of diffuse large B-cell lymphoma (DLBCL).
Of the 55 patients with vitreous specimens available for review, 3 (5%) had a DLBCL infiltration in the vitreous without any central nervous system involvement as a manifestation of systemic lymphoma. All 3 patients were men, aged 54, 66, and 73 years, and had blurred vision and floaters for several weeks before undergoing diagnostic vitrectomy. Ophthalmic examinations revealed clumps of vitreous cells but no choroidal involvement. One patient had no history of lymphoma; the diagnosis of vitreoretinal lymphoma was followed by DLBCL after a lymph node biopsy. The other 2 patients had low-grade B-cell lymphoma and chronic lymphocytic leukemia for 29 and 7 months before large-cell transformation in the eye. Patients were treated with systemic chemotherapy plus intraocular injections of rituximab or methotrexate sodium.
Conclusions and Relevance
Vitreoretinal symptoms of DLBCL in patients with systemic lymphoma may be more frequent than previously thought (5% in our study). Not all lymphomas with vitreoretinal involvement represent primary intraocular lymphomas; thorough ophthalmologic evaluation in patients with visual symptoms and complete staging in patients with documented ocular lymphoma are of utmost importance.
The concept and understanding of intraocular lymphomas has changed greatly in the past several years. Intraocular lymphomas are now known to represent a diverse group of hematologic malignant neoplasms involving different tissues within the eye, each with different morphologic, immunophenotypic, genetic, and clinical features.1,2 Therefore, Chan et al3 have proposed that intraocular lymphomas be classified according to the tissue of involvement (eg, iris, ciliary body, choroid, or vitreoretinal) and whether they are primary or secondary to systemic lymphoma.
Primary intraocular lymphoma is considered a rare subset of primary central nervous system (CNS) lymphoma and most recently has been termed primary vitreoretinal lymphoma because of its frequent clinical appearance with mainly vitreoretinal infiltrates. Secondary ocular involvement by systemic lymphoma most commonly involves the choroid.
Predominant involvement of the retina and vitreous without uveal infiltration in a patient with systemic lymphoma, mimicking a primary vitreoretinal lymphoma, is extremely rare.2 We examined our institutional experience with this phenomenon by reviewing the records of patients undergoing diagnostic vitrectomy for suspected malignant neoplasm during an 11-year period.
We obtained Mayo Clinic institutional review board approval for this study. All patients described had granted permission for research use of their data.
We performed a computer-based search of our pathology database for all cases of vitreoretinal lymphoma diagnosed by vitreous aspiration biopsy findings at the Mayo Clinic from January 1, 2000, through December 31, 2010. Cases of secondary involvement of the vitreous body by systemic lymphoma were identified. This study focused only on cases in which the vitrectomy specimen was the initial specimen in which diffuse large B-cell lymphoma (DLBCL) was diagnosed.
We reviewed the electronic medical records of all patients identified to obtain demographic information, clinical history, results of slitlamp examination, radiographic findings, surgical procedures, treatment, and follow-up. The pathology specimens, vitreous aspiration biopsy specimens, and tissue biopsy findings were reviewed to confirm the diagnosis. At the time of the diagnosis, the vitreous aspiration biopsy specimens were prepared as cell blocks, and immunophenotypic studies were performed in paraffin-embedded tissue following standard procedures.4 Antibodies used for immunophenotyping are given in Table 1. In situ hybridization for Epstein-Barr virus (EBV)–encoded messenger RNA was also performed on paraffin sections using methods described previously.5
From January 1, 2000, through December 31, 2010, 57 vitreous aspiration specimens were collected for diagnosis in our laboratory from 55 patients (31 women and 24 men) ranging in age from 23 to 92 years (Table 2). Findings in most of the specimens (36 specimens from 34 patients) were negative for a malignant neoplasm; 20 specimens had positive findings for (n = 17) or findings suggestive of (n = 3) malignant disease. Findings in 1 specimen were considered nondiagnostic. Of the 17 specimens considered positive for malignant disease, 13 represented malignant lymphomas (Figure 1). The details of the clinical findings, treatment, and follow-up in these 13 patients are provided in Table 3. Seven of these were primary vitreoretinal lymphoma (also known as primary intraocular lymphoma), and the other 6 patients had vitreoretinal involvement by systemic lymphoma. In this latter group, 3 patients had concomitant CNS and ocular involvement. In the other 3 patients, all with DLBCL, the vitrectomy specimen was the diagnostic specimen, and no CNS involvement was found at the time of the diagnosis in the vitreous. The clinical findings were unusual in all 3 of these cases, as described in the following reports of cases.
In September 2008, a 54-year-old man with a several-week history of bilateral blurred vision, eye redness, and no other symptoms was examined at Mayo Clinic. He had been treated at another institution for anterior and posterior uveitis with prednisone, without response. An ophthalmic examination at our institution revealed the presence of anterior chamber and vitreous cells without choroidal involvement or inflammatory signs (Figure 2A). The patient underwent a diagnostic vitrectomy of the right eye on October 1, 2008. Test results showed a cellular specimen represented mostly by large atypical lymphoid cells that were positive for Pax-5, CD20, and CD79a immunostaining; negative for CD3; and with a high proliferation index highlighted by MIB-1 positivity for Ki-67 (Figure 2B-D). On the basis of these findings, a diagnosis of large B-cell lymphoma (LBCL) was made. Later, in situ hybridization for EBV was performed to exclude an EBV-driven lymphoproliferative process, and the results were negative.
Subsequent staging studies showed evidence of positron emission tomography–avid lymphadenopathy in the right aspect of the neck and a mesenteric soft-tissue mass. The lymph node from the right aspect of the neck underwent biopsy a week later. The tissue showed marked distortion of the node architecture with patchy areas of infiltration by a population of large atypical cells, some with markedly pleomorphic nuclei or multinucleation (Figure 2E). Many showed abundant amphophilic cytoplasm with a perinuclear hof (perinuclear clearing). In some areas, these cells were associated with residual follicles. The tumor cells were positive for CD20, MUM1, and anti–human Bcl-2 oncoprotein antibodies; showed weak positivity for CD45; and were λ light chain restricted. Occasional tumor cells were positive for EBV. The tumor cells were negative for all the other markers tested (CD3, CD138, ALK1, CD15, CD21, CD2, Bcl-6, CD30, and CD10), consistent with the diagnosis of DLBCL. Other results included no evidence of lymphoma on bone marrow biopsy findings, a lactate dehydrogenase level of 234 U/L (to convert to microkatals per liter, multiply by 0.0167), negative findings of cerebrospinal fluid cytologic examination, and no evidence of brain abnormalities on magnetic resonance imaging (MRI) of the head.
Chemotherapy was initiated with high-dose methotrexate sodium, but acute renal failure developed after the first dose, which required prolonged hospitalization. The patient then was treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxyl-daunorubicin], vincristine sulfate [Oncovin], and prednisone) regimen. His visual symptoms in the right eye improved, but he still reported blurred vision in the left. He was treated with bilateral intravitreal injections of rituximab and intravitreal triamcinolone diacetate. A posterior retinal detachment developed in the left eye as a result of a retinal tear. After completing 6 cycles of R-CHOP chemotherapy, results of follow-up testing revealed complete remission.
In March 2009, the patient received an autologous stem cell transplant. His 12-month evaluation revealed no evidence of systemic or ocular lymphoma. In September 2010, optical coherence tomography showed slight retinal elevations due to the presence of subretinal and retinal infiltrates in the right eye (Figure 2F). Another vitreous aspiration biopsy of the right eye in October 2010 confirmed the persistence or recurrence of LBCL. Immunostudies performed in the vitreous specimen showed that the neoplastic cells were positive for CD20, CD79a, Pax-5, and MUM1. In situ hybridization findings for EBV were again negative. Magnetic resonance imaging of the head showed no CNS lymphoma. He was treated with bilateral intraocular methotrexate and rituximab injections and followed up with measurements of interleukin 10 levels in the vitreous and aqueous fluid. At his last follow-up visit in January 2012, the patient was in systemic remission without evidence of CNS disease on MRI, but he had a few remaining vitreous cells bilaterally. He continues to receive intravitreal injections, although no evidence of increasing cells in the vitreous body and no CNS involvement have been detected.
A 66-year-old man had had severe fatigue for approximately 2 years. During a workup for hypochromic microcytic anemia in May 2007 at another institution, a bone marrow biopsy was performed, which led to a diagnosis of a low-grade B-cell lymphoma suggestive of marginal zone lymphoma. This represented a κ light chain–restricted clonal B-cell lymphoma, with cells positive for CD19 and CD20 and negative for CD5 and CD10. The patient was treated with 5 cycles of CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy. Results of a bone marrow biopsy in July 2009 showed persistent involvement (50%) by low-grade lymphoma.
In September 2009, blurry vision developed in his right eye. The patient was examined by his local ophthalmologist and referred to a neuro-ophthalmologist at another institution, who, on examination, believed that there were floaters in the vitreous. The patient first visited Mayo Clinic in October 2009. On ophthalmic examination, the patient had vitreous cells but no evidence of choroidal involvement. Results of a vitreous aspiration and a biopsy of the right eye revealed vitreous involvement by B-cell lymphoma. Although the cells were markedly degenerated, they were atypical lymphoid cells that were positive for CD20 and CD79a and negative for CD3 and CD68 on immunostudy findings. The patient was treated with intraocular methotrexate injections.
In January 2010, the patient became acutely confused at work and was found to have a new 4-cm intracranial lesion. Results of peripheral blood and bone marrow biopsy revealed the persistence of his low-grade B-cell lymphoma. He was treated with intravenous high-dose methotrexate. In July 2010, he was found to have bilateral testicular involvement by DLBCL, germinal center phenotype, per the immunohistochemical algorithm of Hans and colleagues.6,7 Results of immunostudies showed that the atypical lymphocytes were positive for CD20, CD10, Bcl-6, and MUM1, with a proliferation rate of 30% to 40% by MIB-1 staining. In August 2010, MRI indicated multifocal CNS disease, and a vitreous aspiration biopsy of the left eye revealed recurrence of LBCL, with cells positive for CD20 and CD79a on immunostaining. The patient was referred for whole-brain and ocular radiotherapy and decided to pursue treatment closer to home. The patient died of his disease in November 2010, 14 months after his diagnosis of ocular involvement by lymphoma.
A 73-year-old man received a diagnosis of chronic lymphocytic leukemia in May 2009 at another institution. No treatment was undertaken. In October 2009, he noticed bilateral blurred vision and was found to have floaters in both eyes. He underwent a diagnostic vitrectomy elsewhere, the results of which were considered nondiagnostic. A diagnosis of autoimmune retinopathy was considered, and the patient was treated with prednisone, resulting in transient mild improvement of his vision. However, his vision progressively worsened and frontal headaches developed. A head MRI showed normal findings.
During his first evaluation at Mayo Clinic in April 2010, the patient was found to have vitreoretinal infiltrates (Figure 3A and B), for which he underwent a left vitreous aspiration and retinal biopsy. Results of the retinal biopsy were not diagnostic; however, the vitreous aspiration biopsy revealed large atypical lymphocytes that were positive for CD20 and CD79a on immunostaining, consistent with LBCL (Figure 3C and D). Staging studies showed a white blood cell count of 31 500/μL and lymphocytosis of 6540/μL (to convert white blood cell counts to ×109 per liter, multiply by 0.001), and the peripheral blood flow cytometry was consistent with κ light chain–restricted chronic lymphocytic leukemia. Magnetic resonance imaging of the head revealed a heterogeneously enhancing mass in the posterior superior right parietal lobe and additional enhancement within an adjacent splenium of the corpus callosum bilaterally, which was radiologically suggestive of CNS lymphoma. Cytologic examination of the cerebrospinal fluid was negative for a malignant neoplasm.
The patient initiated high-dose systemic methotrexate therapy, which was complicated by the development of renal failure with subsequent dose reduction. On relapse of LBCL, the patient was treated with rituximab and temozolomide. Because of progressive disease, including vitreoretinal involvement, he underwent whole-brain and ocular radiotherapy. The patient also received intraocular injections of methotrexate. In June 2010, the patient reported worsening of his overall symptoms, including visual symptoms, and an MRI of the head revealed progression of the CNS disease. The patient was last examined at Mayo Clinic in October 2010. He elected to seek treatment closer to his home. Through correspondence, we learned that the patient died in May 2011.
In this study, we report our institutional experience with a vitreous presentation of DLBCL, mimicking primary vitreoretinal ocular lymphoma, in patients with systemic lymphoma. This phenomenon was seen in 3 of 55 patients undergoing diagnostic vitrectomy during an 11-year period. In 1 patient, the ocular symptoms and subsequent diagnostic vitrectomy led to the diagnosis of systemic DLBCL. This patient had persistent ocular lymphoma with no CNS involvement and was free of systemic disease at 40 months of follow-up. In the other 2 patients, the vitreous cavity was the primary site of large-cell transformation of low-grade B-cell malignant neoplasms and was followed only subsequently by CNS involvement and, ultimately, death. These findings indicate the importance of ophthalmologic studies in patients with lymphoma who have visual symptoms and of comprehensive staging studies in patients with documented vitreous lymphoma.
Intraocular lymphomas are rare, accounting for less than 1% of all non-Hodgkin lymphomas.8 Most publications report single cases or small series.9- 13 The large reports are usually multi-institutional collaborations.3,14 Our understanding of this entity has greatly changed as the result of better diagnostic techniques, such as optical coherence tomography that allows for more precise localization of the process in the ocular tissues involved, and advances in the field of hematopathology, with immunophenotyping and molecular techniques allowing diagnosis in smaller samples and in specimens with fewer cells. Intraocular lymphoma is now known to represent a diverse group of hematologic malignant neoplasms—thus, the proposal to classify them according to the tissue of involvement and whether they are primary or secondary to a CNS or systemic lymphoma.3
Primary vitreoretinal lymphoma is characterized by vitreous or retinal infiltrates or both and has been considered a subset of primary CNS lymphoma. Approximately 15% to 25% of patients with primary CNS lymphoma eventually develop vitreoretinal involvement in the course of their disease.8,15 Conversely, brain involvement will develop in an even higher percentage of patients with primary vitreoretinal lymphoma—56% to 90%—in the course of their disease.14,16
The secondary form of intraocular lymphoma (ie, ocular involvement in the setting of systemic lymphoma) usually manifests with choroidal infiltrates in the latter stages of the disease.8 Our series emphasizes that systemic evaluation is important for patients with vitreoretinal lymphoma.
The diagnosis of vitreoretinal lymphoma requires histologic confirmation.17,18 Vitreous aspiration biopsy has been the preferable diagnostic procedure; however, its reported sensitivity has varied greatly in different studies from 31%19 to 87.5%.11 Multiple diagnostic procedures may be required before an unequivocal diagnosis can be made, especially if vitreous body involvement by neoplastic cells with intermixed reactive cells is minimal16 or if the neoplastic cells are markedly degenerated.11,20
The World Health Organization has developed guidelines for classifying intraocular lymphomas that rely on the synthesis of clinical, histologic, phenotypic, and genetic features. Immunophenotyping can be performed using flow cytometry or immunohistochemistry.8,11,16,17 Polymerase chain reaction analysis of B- or T-cell receptor genes to assess clonality can increase diagnostic sensitivity in specimens with fewer cells.21,22 The most frequent type of vitreoretinal lymphoma is DLBCL with a nongerminal center B-cell phenotype as defined by the Hans algorithm (negative for CD10 and Bcl-6 or positive for MUM-1 and Bcl-6 without expressing CD10).6,11,21 Intraocular vitreoretinal T-cell lymphomas have been reported rarely, with most cases representing secondary intraocular involvement10- 12 but with occasional primary tumors being described.23
Large-cell transformation of low-grade B-cell malignant neoplasms usually heralds clinically aggressive behavior and is associated with poor prognosis.24,25 In chronic lymphocytic leukemia, such transformation is known as Richter syndrome and occurs in about 5% of patients.25 The presenting sites of large-cell transformation in these patients are usually hematologic tissues, such as lymph nodes and bone marrow, and rarely occur in other sites, such as the gastrointestinal tract,26 CNS,27- 29 and skin.30 Ocular involvement by Richter syndrome is rare, with only 1 case reported in the literature.31 In this report, we describe 2 patients with systemic low-grade B-cell malignant neoplasms in whom the first site of detection of large-cell transformation was the vitreous cavity. In both patients, eye involvement preceded the detection of CNS involvement.
The treatment of vitreoretinal lymphoma has not been uniform among institutions. Treatment modalities vary, including local treatment (intraocular methotrexate or rituximab), regional treatment (whole-brain and ocular radiotherapy), systemic treatment (chemotherapy), or a combination of these. Eradication of the intraocular disease is believed to be important to eliminate the eye as a reservoir of untreated disease that might increase the risk of recurrence.14 Dedicated treatment of the intraocular lymphoma alone does not seem to improve survival.14,15,32
Patients with vitreoretinal lymphoma have a limited life expectancy, as shown in several reports and by an international collaborative study group with 83 patients.14 The median progression-free and overall survival in the latter group were 29.6 and 58.0 months, respectively, unaffected by treatment type. Treatment can induce remission, but disease relapses are common and cure is rare.8
In summary, although systemic involvement in patients with vitreoretinal lymphoma is rare, as demonstrated in 5% of patients in our series, our study emphasizes the importance of systemic evaluation in addition to CNS evaluation in all patients with a diagnosis of vitreoretinal lymphoma.
Submitted for Publication: November 23, 2012; final revision received January 24, 2013; accepted January 25, 2013.
Corresponding Author: Diva R. Salomão, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email@example.com)
Published Online: June 6, 2013. doi:10.1001/jamaophthalmol.2013.334.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported in part by an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness and by the Mayo Foundation.
Previous Presentation: This study was presented as a poster at the annual meeting of the United States and Canadian Academy of Pathology; February 26 to March 4, 2011; San Antonio, Texas.