presentation of primary intraocular lymphoma

An official website of the United States government

The .gov means it's official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Publications
Account settings
Browse Titles

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Primary intraocular lymphoma.

Sriram Simakurthy ; Soumya Jena ; Koushik Tripathy .

Affiliations

Last Update: August 25, 2023 .

Continuing Education Activity

Primary intraocular lymphoma is a subset of the primary central nervous system lymphoma characterized by monoclonal proliferation of lymphocytes. It is a very rare ocular neoplasm with high morbidity and mortality. This activity describes the signs useful in the evaluation and treatment of primary intraocular lymphoma. It highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Describe the etiology of primary intraocular lymphoma.
Summarize the relevant history and clinical findings of patients with primary intraocular lymphoma.
Review the evaluation process of patients with primary intraocular lymphoma.
Outline the management and interprofessional care of patients with primary intraocular lymphoma.
Introduction

Primary intraocular lymphoma (PIOL) is a rare ocular malignancy and is considered as a subset of primary central nervous system lymphoma (PCNSL) with ocular involvement. [1] It is an extranodal non-Hodgkin, diffuse large B cell lymphoma. It was earlier known as “malignant lymphoma of the uveal tract” and “reticulum cell sarcoma,” which was misleading, and hence, these names went out of vogue. As vitreoretinal manifestations predominate, it is also known as primary vitreoretinal lymphoma (PVRL) or primary central nervous system lymphoma-ocular or ophthalmic variant (PCNSL-O) in literature. [2] [3] [4] [5]

Secondary intraocular lymphoma arises outside the central nervous system or eye and later metastasizes to the eye. [6] The lymphoma cells here predominantly involve the uveal tissue. [7] Primary uveal lymphoma is a less common entity involving B cell infiltration of the uveal tract and belongs to the extranodal marginal zone or mucosa-associated lymphoid tissue lymphoma. [8] It is distinct from PIOL of diffuse large B cells and carries a better prognosis. [9]

The etiopathogenesis of primary intraocular lymphoma is still not well understood.

Chemokine theory – B cell chemokines such as B-lymphocyte chemoattractant (BLC) and stromal cell-derived factor-1 (SDF-1) present in retinal pigment epithelium (RPE) attract lymphoma cells from the choroidal circulation to RPE. [10]

Infection theory – Infectious agents are known to cause lymphocyte proliferation which later turns into clonal proliferation. Epstein-Barr virus (EBV) infection of the B lymphocytes results in uncontrolled proliferation of the lymphocytes in the absence of T- suppressor lymphocytes in immunodeficiency states such as AIDS (acquired immunodeficiency syndrome). [11] This is supported by the invariable presence of EBV in AIDS patients with PCNSL. However, a similar association has not been noted in immunocompetent individuals with PIOL. [12] Similarly, Toxoplasma gondii DNA has been detected in B cell lymphoma cells of PIOL. [13]

Epidemiology

The exact epidemiology of PIOL is not known. Most of the available data relates to a larger group of primary central nervous system lymphoma. PCNSL accounts for 1 to 2% of all extranodal lymphomas and 3 to 5% of primary CNS (central nervous system) tumors. [14] It is more commonly seen in immunocompromised individuals. [15] However, with the advent of highly active antiretroviral therapy (HAART), its incidence among immunocompromised individuals has come down. [16]

Primary intraocular lymphoma usually occurs in adults from the third to eighth decade of life, with a mean age of presentation in the fifth and sixth decades of life. [17] Few cases have been reported in extremes of age group. In Immunocompromised individuals, PIOL occurs in younger individuals. [18] There are no known racial or ethnic associations. Women are more commonly affected than men in the ratio of 2 to 1. [19]

Pathophysiology

Most primary intraocular lymphomas originate from B lymphocytes (late germinal or post germinal center). [20] Very rarely, PIOLs may have T cell origin. [21] Primary CNS lymphoma originates from late germinal or post-germinal center lymphoid cells with neurotrophic localization to the central nervous system. The trafficking of lymphoma cells from brain to eye and vice versa involves direct invasion of the optic nerve, presence of common venous drainage, or common integrin expression. [22]

History and Physical

Primary intraocular lymphoma is a great masquerader and can mimic nonspecific uveitis. The delay between the onset of symptoms (ocular or CNS) and a positive diagnosis usually varies from 4 to 40 months. [23] About ¼th of patients with PCNSL will have concomitant vitreoretinal lymphoma at the time of diagnosis. [24] Conversely, 56 to 90% of individuals with vitreoretinal lymphoma will develop CNS involvement over a follow-up period of 8 to 29 months. [25] At the initial presentation of PIOL, about 16 to 34% of patients tend to have central nervous system involvement. [26]

Ophthalmic Findings

The most common symptom is a painless blurring of vision or a complaint of floaters. The disease is bilateral in 80% of the individuals and is asymmetric in presentation. [27] Anterior segment findings include cells in the anterior chamber, keratic precipitates, infiltration of iris or angle, and rarely pseudohypopyon. Posterior segment findings can mimic choroiditis or vasculitis and include vitritis, which is surprisingly responsive to topical and oral steroids initially. The vitreous cells may form clumps, sheets, or strands leading to media haze. The cells in PIOL are larger than inflammatory cells. These cells do not cluster with reactive cells. They are arranged along vitreous fibrils in the form of linear opacities giving rise to the "aurora borealis "appearance of vitreous or a "string of pearls" appearance, which includes fine fibrils connecting bunches of inflammatory material. [28] [29]

Creamy lesions with yellowish-orange subretinal or sub-RPE infiltrate may be seen, leading to "leopard skin pigmentation" over the lesions. [30] This may be associated with exudative retinal detachment. Spontaneous resolution may lead to RPE atrophy and subretinal fibrosis. [31] Posterior synechiae formation and scleral inflammation are not frequently seen in PIOL. [17] In contrast to other uveitic conditions with a similar degree of inflammation, cystoid macular edema is often absent, and vision is comparatively preserved. [32] Orbital involvement in PIOL is exceptionally rare and helps in differentiating it from simulating lesions. [33]

Central Nervous System (CNS) Findings

The new onset of seizures indicates CNS involvement in a case of PIOL. [34] Symptoms can be either focal or diffuse. The most common focal symptoms include hemiparesis (51%) and cerebellar ataxia (23 %). [24] Involvement of the frontal lobe leads to behavioral changes and cognitive impairment. [35]

Biopsy & analysis
Blood tests

Optical coherence tomography (OCT) Fundus fluorescein angiography (FFA)

Optical coherence tomography (OCT): It is helpful to demonstrate or analyze lesions at the posterior pole. Findings include nodular hyperreflective lesions in the retinal pigment epithelial layer corresponding to subretinal and sub-retinal pigment epithelium (RPE) lymphoma deposits ( Figure 1 ). [36] It is also useful to confirm the absence of cystoid macular edema. [32] The images are usually difficult to capture as the ocular media is usually hazy due to vitreous involvement.
Fundus Fluorescein angiography (FFA): Findings in FFA include small hypofluorescent lesions in the early and late phase corresponding to infiltrates masking the choroidal fluorescence, with late staining at the level of RPE in another series. [37] other findings include punctate hyperfluorescent window defects, vasculitis, and very rarely petaloid leak at the macula. [32] [17]
Indocyanine green angiography (ICGA): It shows small hypofluorescent lesions in the early phase, which become less apparent in late phases. The hypofluorescent lesions are more numerous in FFA compared to ICGA. [32]
Fundus Autofluorescence (FAF): Sub-RPE pigment clumps that give rise to "leopard spotting" appearance are hyperautofluorescent, whereas white lesions above the RPE are hypoautofluorescent. [21] Granularity on FAF is noted in cases with active lymphoma. [38]
Ocular ultrasound: There are no definitive findings of PIOL on ocular ultrasonography. The most common ultrasound findings in the case of PIOL include vitreous echoes, elevated chorioretinal lesions, and retinal detachment. [39]
Neuroimaging: Computed tomography (CT) and magnetic resonance imaging (MRI) imaging of the brain show unifocal or multifocal periventricular, homogenously contrast-enhancing lesions. [40] [41] In CT imaging, the lesions are isodense or hyperdense, while in MRI, lesions are hyperintense on T1 imaging and iso-hyperintense on T2 imaging. [42]

II. Biopsy and Analysis

The definitive diagnosis depends on the demonstration of the malignant lymphoma cells in the ocular specimens (vitreous, aqueous, chorioretinal biopsy) or the cerebrospinal fluid (CSF). [4] Typically lymphoma cells are present between RPE and Bruch's membrane; however, the lymphoma cells invade the vitreous, and hence vitreous sampling also helps in evaluation. A chorioretinal biopsy is often indicated if there is an absence of anterior chamber or vitreous cavity inflammation, the presence of a fovea threatening lesion that is non-responsive to treatment, infection with equivocal results on prior testing, or in cases with a strong suspicion of neoplasm. [43] Multiple biopsies may sometimes be needed to reach a definitive pathological diagnosis. Uveal biopsies are often nondiagnostic.

Ocular Biopsy

Technique: Techniques of ocular biopsy include fine-needle aspiration of vitreous via pars plana (21G to 25G), pars plana vitrectomy, transscleral biopsy for subretinal lesions, anterior chamber tap, and enucleation. Vitrectomy has added advantage of clearing vitreous debris, maximizing sample collection, and access to subretinal space, although there is a risk of extension of lymphoma through the sclerotomy site to peribulbar space. [44] [45] In cases of a painful blind eye, a diagnostic enucleation may be performed. [46]

Techniques to increase the diagnostic yield include

Any corticosteroid use should be discontinued for at least two weeks before the biopsy. [47]
Precautions during vitrectomy include the use of large-bore cutters and a low cut rate to reduce the shearing of cells.
Collect undiluted fresh vitreous with infusion off.
Since lymphoma cells undergo morphological degeneration within 60 minutes, the sample should be transported to the laboratory quickly.
Fixation of the sample in HOPE (HEPES-glutamic acid buffer-mediated Organic solvent Protection Effect) solution may increase the yield. [48]

Cerebrospinal Fluid (CSF) and Brain Biopsy

A lumbar puncture can be done to obtain CSF in cases with suspected PCNSL. In cases with a positive yield on CSF and if an intraocular lesion suspicious of PIOL is present, the need for ocular tissue biopsy is less important unless the intraocular process does not respond to the treatment initiated. [43] Stereotactic brain biopsy is done in patients with negative CSF cytology and suspicious brain lesions on imaging. [49]

Histopathology: Histopathological analysis reveals a monoclonal population of large B cells with scanty cytoplasm, high nuclear: cytoplasmic ratio, hypersegmented round, oval, or clover-shaped nuclei with coarse chromatin pattern, and prominent or multiple nucleoli ( Figure 2 ). [26] [45] Cytological evaluation has a high positive predictive value of 99 – 100% and a negative predictive value of 61 to 81%. [50] [51] Challenges in histopathological analysis of specimens include the presence of a sparse number of cells, confounding features such as T lymphocytes, necrotic cells, and fibrin. [26]
Immunohistochemistry and flow cytometry: The presence of a monoclonal population of a single immunophenotype supports the histopathological diagnosis. Most cases of PIOL are monoclonal B cell lymphomas and stain positively for B cell markers like CD19, CD20, CD 22, and germinal center markers such as BCL 6 and CD 10. [52] [53] Reactive inflammatory cells tend to be T cells and express CD 3 and CD 5. [25] Hence in a rare case of T cell PIOL, the distinction between inflammation and tumor is mainly based on morphology and demonstration of monoclonality. [54]
Cytokines : B cells secrete high amounts of interleukin (IL) IL-10, an immunosuppressive cytokine. [55] [56] On the other hand, in uveitis, the vitreous is rich in IL-6, a pro-inflammatory cytokine. [56] Intravitreal IL-10: IL-6 ratio>1 has 75% sensitivity of distinguishing PIOL from uveitis. [57]
Polymerase chain reaction (PCR): In cases of PIOL, monoclonality of the B cell population can be detected using framework regions (FR)- FR2, FR3, and complementarity determining regions 3 (CDR3) primers. [58] Monoclonality of rare T cell PIOL can be detected through T-cell receptor (TCR) gene rearrangements. [7]

Given the paucity of vitreous available for testing, the histopathological analysis gets precedence, and the supernatant sample can be sent for cytokine analysis. [56] The sample can then be sent for immunohistochemistry/flow cytometry and PCR analysis, depending on the available sample amount.

III. Blood tests: These are basically done to rule out infective causes of uveitis such as syphilis, tuberculosis, herpes, toxoplasmosis, HIV (human immunodeficiency virus) status; inflammatory disorders such as sarcoidosis, Vogt Koyanagi Harada disease, Behçet, and also to look at side-effects of systemic chemotherapy.

Treatment / Management

Treatment goals include controlling the local disease along with preventing CNS dissemination. Treatment modalities include intravitreal injections, chemotherapy, and radiotherapy, used alone or in combination. Chemotherapy is considered the first-line therapy for PCNSL. [59] International PCNSL collaborative group recommends systemic therapy for PIOL with CNS involvement and local therapy for disease localized to the eye. [28] Therapies commonly used in systemic lymphomas are not commonly successful in PCNSL and PIOL.

Local Therapy

Intravitreal Methotrexate (MTX)

Dose: 0.4 mg in 0.1 ml [60]

Indications:

Unilateral/Bilateral PIOL
In combination with systemic chemotherapy for PVRL with CNS involvement
Relapsed PIOL
Ocular relapse of PCNSL

The therapeutic dose of intravitreal MTX is maintained in the vitreous for five days. [61] The most common administration scheme of intravitreal methotrexate is twice weekly for four weeks in the induction phase, weekly for eight weeks in the consolidation phase, and monthly for another nine months in the maintenance phase with a total of 25 injections. [60] A mean of 6.4 injections was needed to reach remission, with 95% of cases receiving 13 injections or less. [60]

The common complications of intravitreal MTX include cataracts, corneal epitheliopathy and maculopathy, limbal stem cell damage, optic atrophy, and sterile endophthalmitis. [53] An aqueous paracentesis should be done to avoid subconjunctival extravasation, which can lead to pain, irritation, and corneal epitheliopathy. [62]

Intravitreal Rituximab

Dose: 1 mg in 0.1 ml [63]

It is an anti-CD20 monoclonal antibody, given as an intravitreal injection. There is a lack of standardization of treatment schedules varying from a single injection to multiple injections at variable intervals. [64] It is usually given as four-weekly intervals. [64] [65] The primary response is usually good, but subsequent relapses may require intravitreal methotrexate and radiation. [63] Complications related to intravitreal injection of rituximab include cataract formation, increased intraocular pressure, granulomatous anterior uveitis, vitreous hemorrhage, and retinal detachment. [64]

Radiation Therapy

External beam radiotherapy is given to patients with PIOL without CNS involvement. [28] Traditionally given in the dose of 54Gy, but due to increased risk of radiation retinopathy, the dose has been reduced to 35 to 40 Gy in approximately 15 fractions of 2Gy each, from opposed lateral beams to include both the eyes. [19] [66]

Whole-brain radiotherapy is added with ocular radiotherapy in cases with CNS dissemination and who do not respond to systemic chemotherapy or cannot tolerate aggressive therapies. [66] High dose low fractionation CNS irradiation can cause neurotoxicity, which can present in the form of depression. [67] The ocular side effects of external beam radiotherapy include dermatitis, punctate keratopathy, radiation retinopathy, cataract, optic neuropathy, and dry eye syndrome. [6]

In cases with significant cellular load, this can be considered as an adjunct therapy for debulking. [43] This is often combined with intravitreal chemotherapy.

Systemic Therapy

Chemotherapy

Chemotherapy is the mainstay of the treatment - usually used in combination with radiation therapy or can also be used alone as primary therapy. The main barrier to systemic chemotherapy is penetration via the blood-brain barrier and blood-ocular barrier. Methotrexate and Cytosine arabinoside penetrate the blood-ocular barrier and are commonly used.

Route – Intravenous, Intrathecal

Methotrexate (MTX)

High-dose methotrexate can penetrate the blood-brain barrier, with a complete response rate of 50 to 80%, [68] and is usually included in all chemotherapeutic regimens. It is given in the dose of 8 g/m^2 intravenously. In the induction phase, it is given every 14 days until complete response, every 14 days for two doses in the consolidation phase, and every 28 days for 11 months in the maintenance phase. [69] Intrathecal methotrexate is given in a dose of 12 mg or 6 mg by Ommaya reservoir administered once per cycle. [70]

Systemic MTX can cause ocular complications like periorbital edema, increased lacrimation, photophobia, blepharitis, conjunctival hyperemia, and photophobia. [53] Intrathecal methotrexate plays a role in cases with PIOL with CNS involvement. [71]

Cytosine Arabinoside (Ara-C)

Cytosine Arabinoside, also used as a chemotherapeutic agent, can penetrate the ocular blood barrier. [72] High-dose Cytosine arabinoside (Ara-C) is given in the dose of 2 to 3 g/m^2 for three months for six cycles. [73] Intrathecal cytarabine is given in a dosage of 100 mg once per cycle. [70] Ocular complications of Ara-C include ocular irritation, conjunctivitis, and keratitis.

Intravenous rituximab is usually given along with methotrexate in cases with relapse/ recurrences of PVRL in the dose of 375mg/sqm. [63] [70]

Combination Chemotherapy

A combination of MTX and Ara-C was used in patients with both ocular and CNS disease by Valluri et al. [74] Both ocular and CNS disease resolved with remission of at least 24 months. [53] MATRix therapy, which is a combination of MTX, cytarabine, thiotepa, and rituximab, has been tried in patients < 70 years of age with good response. [75] It has shown a complete remission rate of 50% compared to groups treated with MTX and cytarabine, where remission rate was 23%, and the group treated with MTX, cytarabine, and rituximab, where remission rate was 30%. [75]

Autologous stem cell transplantation is done in cases of refractory or recurrent PCNSL and PIOL after a course of intensive chemotherapy to rescue from systemic side effects of high-dose chemotherapy. [76]

Drugs Under Ongoing Trials

Pomalidomide

It's a thalidomide-based agent, usually used for systemic diffuse large B cell lymphoma with better penetration to CNS. It has been tried along with dexamethasone systemically for recurrent or refractory CNS and vitreoretinal lymphoma with promising results. The dose-escalation schedule of pomalidomide that followed was 3,5,7,10 mg orally daily for 21 days every 28 days and dexamethasone 40 mg every week. [77]

It is an orally administered agent with significant penetration of the blood ocular/CNS barrier. [70] It acts by inhibiting Bruton tyrosine kinase and HCK tyrosine kinase protein, both of which are upregulated by MYD88 L265P mutation. [53] The presence of this particular mutation is responsible for potential sensitivity to Ibrutinib. It has been tried in the dosage of 560 mg orally once daily for 28 days until disease progression, or unacceptable toxicity occurred. [78] It is usually reserved for patients with relapse or recurrences of PCNSL and PVRL. Ibrutinib with high-dose systemic steroids can lead to invasive fungal and pneumocystis infections. [79]

Lenalidomide plus Rituximab

Lenalidomide and rituximab combination has shown promising results in recurrent/ relapsing PCNSL. [80] The regimen includes eight 28-day cycles of induction phase (lenalidomide 20 mg/day, days 1 through 21 for cycle one followed by 25 mg/day, days 1 through 21 for subsequent cycles in combination with intravenous rituximab 375 mg/m^2 ), and twelve 28-day cycles of maintenance phase (lenalidomide alone in the dose of 10 mg/day, days 1 through 21). [80]

Chemoradiation

Combining chemotherapy with radiation can be used as primary therapy or as salvage therapy in PIOL. [81] Intra-thecal chemotherapy can also be combined with radiation. [82] Multimodal therapy leads to better disease control with delayed cognitive neurotoxicity. [83] Rituximab and methotrexate-based systemic chemotherapy along with intravitreal methotrexate and low dose brain irradiation (23.4Gy) had shown disease-free survival of up to 25 months. [84]

Differential Diagnosis

Diagnosis of PIOL is very challenging as various infectious and non-infectious diseases can mimic the clinical condition. Various differentials include

Inflammatory Diseases

Posterior uveitis/panuveitis
Intermediate uveitis [85]
Sarcoidosis
Vogt Koyanagi Harada disease
Behçet disease
Multifocal choroiditis [86]
Multiple evanescent white dot syndrome
Acute posterior multifocal placoid pigment epitheliopathy
Birdshot choroidopathy
Serpiginous chorioretinopathy
Frosted branch angiitis

Infectious Diseases

Tubercular uveitis
Endophthalmitis [87]
Syphilis [88]
Toxoplasmosis [89]
Acute retinal necrosis [90]
Herpetic uveitis
Amelanotic melanoma
Metastatic cancers

In a study, the most useful signs to differentiate lymphoma from simulating conditions listed above were – better vision, less anterior chamber flare, less posterior synechiae, and less optic disc swelling, retinal vasculitis, or disc involvement. [32]

Treatment Planning

The treatment plan for the management of PIOL is varied, and no common consensus is available. The protocol suggested by Pulido et al. for treatment has been discussed in the following figures ( Figures 3, 4, and 5 ). [70]

PIOL with CNS involvement has a poor ocular prognosis due to the intrinsic aggressive nature of the disease. In PIOL, the mortality rate ranges from 9 to 81% in a follow-up period from 12 to 35 months. [26] According to Hormigo et al., the survival advantage if PIOL was diagnosed before CNS involvement was found to be 60 months versus 35 months if it was found later. [91]

The IELSG score used for PCNSL prognostication is valid only for PVRL with CNS involvement. [75] Primary CNS lymphoma has a poor five-year survival rate of 30%. [92] The median survival in patients with PCNSL, who are treated with radiotherapy alone or chemoradiation, can go up to 10 to 16 months. [93] With methotrexate-based chemotherapy or ifosfamide or trofosfamide, the medial survival rate can go up to 30 months. [93] [94]

In a study by Grimm et al., the patients after receiving a mix of therapies had a median survival of 31 months and median progression-free survival of 18 months, with ocular therapy causing no improvement in chances of survival. [95]

Complications

Unlike other posterior uveitides, which PIOL masquerades, if not detected and treated early, it may progress to CNS involvement with high fatality rates. The use of chemotherapeutic agents to treat the disease presents its own set of systemic and local complications such as pancytopenia, hepatic dysfunction, dry eye, cataract, and radiation retinopathy.

Deterrence and Patient Education

Patients diagnosed with primary intraocular lymphoma should be informed about the risk of central nervous system involvement and its symptoms such as behavioral change, new onset of seizures, hemiparesis, and ataxia.

Enhancing Healthcare Team Outcomes

Due to the high correlation between PIOL and PCNSL, collaboration with a neuro-oncologist, when available, enhances patient care. Baseline screening and periodic evaluation to look for PCNSL by neurologists help identify cases with high-risk mortality and early initiation of aggressive systemic chemotherapy. An ocular pathologist should be consulted before collecting any diagnostic specimens to help handle and process the specimen appropriately.

Review Questions
Access free multiple choice questions on this topic.
Comment on this article.

Figure 1: color fundus picture showing hazy vitreous media with multiple sub retinal yellow deposits and corresponding optical coherence tomography scan showing hyper reflective nodules in sub retinal space Contributed by Simakurthy Sriram, MD

Figure 2: Vitreous specimen collected in syringe and histopathological examination showing uniform population of small lymphocytes Contributed by Sriram Simakurthy, MD

Figure 3: Management of unilateral primary vitreoretinal lymphoma (PVRL) without central nervous system (CNS) involvement; MTX=methotrexate Contributed by Soumya Jena

Figure 4: Management of bilateral primary vitreoretinal lymphoma (PVRL) Contributed by Soumya Jena

Figure 5: Management of vitreoretinal lymphoma (VRL) with the involvement of central nervous system (CNS) Contributed by Soumya Jena

Disclosure: Sriram Simakurthy declares no relevant financial relationships with ineligible companies.

Disclosure: Soumya Jena declares no relevant financial relationships with ineligible companies.

Disclosure: Koushik Tripathy declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Simakurthy S, Jena S, Tripathy K. Primary Intraocular Lymphoma. [Updated 2023 Aug 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

In this Page

Bulk download.

Bulk download StatPearls data from FTP

Related information

PMC PubMed Central citations
PubMed Links to PubMed

Recent Activity

Primary Intraocular Lymphoma - StatPearls Primary Intraocular Lymphoma - StatPearls

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Connect with NLM

National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894

Web Policies FOIA HHS Vulnerability Disclosure

Help Accessibility Careers

Create account

Intraocular Lymphoma

Primary intraocular lymphoma often poses a diagnostic dilemma with presentation like vitritis, intermediate uveitis or subretinal plaque-like lesions [1] . Diagnosis is often challenging in such cases, and this is why it is often one of the diseases referred to as a masquerade syndrome. [1] [2]

1.1 Etiology
1.3 Symptoms
1.4.1 Fluorescein Angiography
1.4.2 Optical coherence tomography
1.4.3 Fundus autofluorescence
1.4.4 Diagnostic vitrectomy
1.5 Systemic Evaluation
2.1.1 EBRT(External Beam Radiotherapy)
2.1.2.1 Methotrexate
2.1.2.2 Rituximab
2.1.3.1 Methotrexate
2.1.3.2 Rituximab
2.2 Prognosis
3 Additional Resources
4 References

Vitreoretinal lymphoma (as primary introacular lymphoma is now known) is the most common introacular lymphoproliferative disease. The term vitreoretinal lymphoma distinguishes it from other introcular lymphoproliferations including choroidal lymphomas (which do not have any association with central nervous system disease) and iris or ciliary body lymphomas. [3] The term intraocular lymphoma was first introduced more than 60 years ago. [4] [5] However, prior to the advent of immunohistochemistry, vitreoretinal lymphomas were known as reticulum cell sarcomas, microgliomas, perithelial sarcomas or lymphosarcomas. It is considered a variant of primary central nervous system (CNS) lymphomas and may occur only in the eye initially (thus a primary vitreoretinal lymphoma) or contemporaneously with CNS disease. Rarely, a vitreoretinal lymphoma can be classified as secondary when it arises due to metastasis from a systemic lymphoma. [2] [6]

The majority of vitreoretinal lymphomas are of a diffuse large B-cell (DLBCL) histologic subtype [3] [7] [8] , though occasionally T-cell lymphomas can occur. [9]

Vitreoretinal lymphomas represent < 1% of all intraocular tumors [10] , 4-6% of all intracranial tumors and 1-2% of all extra nodal non-Hodgkin’s lymphomas. [11] Involvement of the CNS is common, developing in 35-90% along the course of the disease. Women are more commonly affected than men [10] and patients generally present in 4th to 6th decade [11] , although a case as young as 15 years has been reported [12] [13] . Eighty to ninety percent patients will have bilateral disease, although initial presentation may be unilateral or asymmetric. [11]

On examination , anterior segment is may exhibit anterior chamber cells as well as keratic precipitates in both the primary presentation as well as in recurrences. [14] [2] Confocal microscopy of such "keratic precipitates" has demonstrated features that recapitulate atypical large lymphocytes with large nuclei and minimal cytoplasm. [15] These cells can even layer and present as a hypopyon; in these situations, the eye is generally more quiet than it would be with a hypopyon from an infectious etiology.

The manifestation of the disease can be either as vitreous inflammation, subretinal lesions, or both. Vitreous opacities may be seen extending from posterior pole to periphery which may move on movement of the eye producing an image like aurora in the sky [2] caused due to the reactive inflammatory cells in vitreous.

Subretinal lesions may begin as small, yellow to white mounds, which enlarge and expand and further coalesce to produce large yellow sub retinal masses with brown pigmentation in the center known as leopard skin pigmentation. These lesions may become atrophic and shrink with treatment and the passage of time.

The lesions may involve optic disc producing an optic nerve head swelling. Vasculitis with retinal hemorrhages can also be seen. [16] [17] Sheathing of the vessels may be seen which could be reactive or due to lymphoma cells infiltration.

The patient usually presents with the complaints of blurring of vision, floaters, or a combination of both.

Clinical diagnosis

Vitreoretinal lymphoma can be challenging to diagnose due to its uncommon occurrence and the similarities it shares with other uveitic conditions. Diseases that should be considered on the differential diagnosis include chronic endophthalmitis, syphilis, tuberculosis, Behcet disease, birdshot chorioretinopathy, secondary intraocular lymphoma, primary uveal lymphoma, and birdshot chorioretinopathy. Patients may be initially be treated with topical or systemic corticosteroids under the presumption that their presentation represents a posterior uveitis. Because lymphomatous cells are responsive to steroids, the "uveitis" may improve, only to recur with decrease in the dose of steroids or discontinuation of therapy. A diagnostic and therapeutic vitrectomy may result without a diagnosis of a lymphomatous process, particularly when a patient is still using topical or systemic corticosteroids. A study from the National Eye Institute found that patients underwent a mean of 2.1 procedures prior to a diagnosis of vitreoretinal lympoma. Furthermore, they found an average of 13.9 months from onset of symptoms to a confirmed histopathological diagnosis. [18]

Fluorescein Angiography

Hypofluorescence may be seen due to blockage of dye by the tumor cells as well as granular hyperfluorescence and late staining due to damage to the retinal pigment epithelium. The contrast between hypo- and hyperfluorescence has been noted to be reminiscent of leopard spots, but is certainly not pathognomonic for the disease. A leopard spot pattern denoted by hypofluorescent round spots has been observed in 43% of cases. [19]

Optical coherence tomography

Granular subretinal lesions (between Bruch's membrane and the retinal pigment epithelium) can be seen when subretinal lesions exist. OCT can be used to monitor progression or regression of the lymphoma. [20]

Fundus autofluorescence

Many patterns of fundus autofluorescence exist in intraocular lymphoma. A study from the National Eye Institute found that granularity on FAF was associated with active lymphoma in 61% of their cases. [19]

Diagnostic vitrectomy

For diagnosis, the gold standard is cytopathologic inspection of ocular fluid or chorioretinal biopsies. Small gauge vitrectomy may help with the yield and it is important to obtain an undiluted specimen (0.5 - 1 ml) at a low cut rate.

The sample may then be evaluated for:

Immunohistochemistry
Directed polymerase chain reaction (PCR) for gene rearrangements in immunoglobulin heavy chain genes or (if T-cell lymphoma is suspected) T-cell receptor genes [21]
Directed PCR for mutation in the MYD88 gene involving codon L265P [22]
Cytokine measurement

Even after taking the appropriate measures, this can still yield false negative results.

Cytological examination is the gold standard for diagnosis [23] which shows large atypical lymphoid cells with pleomorphic nuclei, scant basophilic cytoplasm and prominent nucleoli. However, Kimura et al showed that cytology was sufficient in only 48% of cases. [24] The reason for such low yields includes the fact that lymphomatous cells may necrose and be misinterpreted.

Directed PCR can also be performed to identify IgH gene rearrangements using FR2A, FR3A, and CDR3 primers [25] . While fine needle or laser capture microdissection is a technique that can help in procuring a relatively pure population of large, atypical lymphocytes, few ocular pathologists routinely perform such a procedure. Immunohistochemistry employing cell markers such as CD20 , CD3, CD79a, and PAX5 can help identify the cell type. Directed PCR for the MYD88 gene (codon L265P) can also be diagnostic of a DLBCL vitreoretinal lymphoma.

Cytokine evaluation assessing for interleukin (IL)-10 compared to IL-6 may also be considered as corroborating a suspicion of lymphoma. IL-10 is an immunosuppressive cytokine while IL-6 is an inflammatory cytokine; an elevated IL-10 /IL-6 ratio is suggestive of lymphoma, although there is a relatively lower diagnostic sensitivity with this test. [26] [27] [20] Aqueous levels of IL-10 are used by some to monitor for recurrence.

Systemic Evaluation

Gadolium enhanced MRI of the brain should be performed to evaluate for intracerebral disease. Care should be coordinated with a neuro-oncologist.

The treatment can be aimed as local therapy which can be radiotherapy to the eye or intracameral / intravitreal agents like (methotrexate and rituximab) or as systemic therapy which can be external beam radiotherapy or systemic chemotherapy.

Medical therapy

Ebrt(external beam radiotherapy).

In cases of bilaterality, EBRT is the most effective treatment [28] . A total dose of 30-40 Gy, divided in the fractions of 1.5 to 2 Gy is often used.The side effects associated are dermatitis, punctate keratopathy , cataract and radiation retinopathy. The 2-year overall and disease-free survival rates were reported to be 74% and 58% respectively. [29]

Local Chemotherapy

Methotrexate.

In unilateral cases, intravitreal methotrexate has been used in the dosage of 400 µg/0.1cc twice weekly for 4 weeks , followed by 1 weekly for 4 weeks, followed by 1 monthly for 12 months. It is used as a primary therapy as an alternative to radiotherapy or for cases of relapse. [30] The risks associated are conjunctival injection and keratopathy. Sometimes these can be very severe which warrants the use of alternatives. Clinical remission is achieved after mean of 6.4 +/- 3.4 injections [31]

Intravitreal rituximab which is a chimeric anti CD20 monoclonal antibody can be used in the dosage of 1mg /0.1 ml in cases which are unresponsive or cannot tolerate methotrexate. [32]

For isolated ocular lymphoma, local chemotherapy and or radiotherapy can be done. In cases of systemic involvement or CNS lymphoma, systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or rituximab-CHOP is done.

Other systemic agents that have been investigated include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy. [33]

Systemic Chemotherapy

Intravenous high dose methotrexate is commonly used in patients with intraocular lymphoma that have CNS or systemic involvement. [34] [35]

In cases with CNS involvement, rituximab may be used in conjunction with high dose methotrexate. [35]

Currently there is no prophylactic method that completely prevents the onset of CNS lymphoma subsequent to vitreoretinal lymphoma. Patients with vitreoeretinal lymphoma must undergo careful and regular surveillance for development of CNS involvement. While the mortality rates vary widely in the literature, the 5-year overall survival rate of primary vitreoretinal lymphoma is less than 25%. In a multicenter study involving 7 different countries, the investigators found that local ocular therapy may help with the tumor control, but did not impact overall survival. In that particular study, the overall survival and median progression-free survival were reported to be 31 and 18 months, respectively. [36]

Additional Resources

Boyd K. Eye Cancer . American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-cancer-list . Accessed March 11, 2019.
Boyd K, Vemulakonda GA. Eye Lymphoma . American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/eye-lymphoma-list . Accessed March 11, 2019.
↑ 1.0 1.1 Grange LK, Kouchouk A, Dalal MD, Vitale S, Nussenbla RB, Chan CC, et al. Neoplastic masquerade syndromes in patients with uveitis. Am J Ophthalmol 2014;157:526‐31.
↑ 2.0 2.1 2.2 2.3 Biswas J, Majumdar PD .Uveitis: An Update .Goto H.Intraocular lymphoma.2016. 93-100
↑ 3.0 3.1 Coupland SE, Damato B. Understanding intraocular lymphomas. Clin Experiment Ophthalmol . 2008;36:564-578.
↑ Cooper, E.L. & Riker, J.L. (1951) Malignant lymphoma of the uveal tract. American Journal of Ophthalmology, 34, 1153–1158.
↑ Qualman, S.J., Mendelsohn, G., Mann, R.B. & Green, W.R. (1983) Intraocular lymphomas. Natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer, 52, 878–886.
↑ 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 Ophthalmo l . 2013;131(9):1151-1158
↑ Coupland SE, Chan CC, Smith J. Pathophysiology or retinal lymphoma. Ocul Immunol Inflamm . 2009;17:227-237
↑ Chan CC, Gonzales JA. Primary Intraocular Lymphoma. New Jersey, London, Singapore, Beinjing, Shanghai, Hong Kong, Taipei: Worl Publishing Co. Pte. Ltd.,2007:1-267
↑ Coupland SE, Anastasssiou G, Bornfeld N, Hummel M, Stein H. Primary intraocular lymphoma of T-cell type: Report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol 2005;243:189-197
↑ 10.0 10.1 Bardenstein DS. Intraocular lymphoma. Cancer Control. 1998;5:317–325.
↑ 11.0 11.1 11.2 Freeman LN, Schachat AP, Knox DL, et al. Clinical features laboratory investigations, and survival in ocular reticulum sarcoma. Ophthalmology 1987;94: 1631-1639.
↑ Cohen IJ, Vogel R, Matz S, et al. Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB). Cancer. 1986;57:6–11.
↑ Wilkins CS, Goduni L, Dedania VS, Modi YS, Johnson B, Mehta N, Weng CY. Diagnostic and Therapeutic Challenge. Retina. 2021 Jul 1;41(7):1570-1576. doi: 10.1097/IAE.0000000000002820. PMID: 32332425.
↑ Hoffman PM, McKelvie P, Hall AJ, Stawell RJ, Santamaria JD. Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye 2003;17:513-521
↑ Zhang P, Tian J, Gao L. Intraocular lymphoma masquerading as recurent iridocyclitis: findings based on in vivo confocal microscopy. Ocul Immunol Inflamm 2018;26(3):362-364
↑ Akpek EK, Ahmed I, Hochberg FH, Soheilian M, Dryja TP, Jakobiec FA, Foster CS. Intraocular-central nervous system lymphoma: clinical features, diagnosis and outcomes. Ophthalmol 1999;106(9):1805-1810
↑ Katoch D, Bansal R, Nijhawan R, Gupta A. Primary intraocular central nervous system lymphoma masquerading as diffuse retinal vasculitis. BMJ Case Rep 2013;1-4
↑ Dalal M, Casady M, Moriarty E, Faia L, Nussenblatt R, Chan CC, Sen HN. Diagnostic procedures in vitreoretinal lymphoma. Ocul Immunol Inflamm. 2014 Aug;22(4):270-6.
↑ 19.0 19.1 Casady M, Faia L, Nazemzadeh M, Nussenblatt R, Chan CC, Sen HN. Fundus autofluorescence patterns in primary intraocular lymphoma. Retina. 2014 Feb;34(2):366-72.
↑ 20.0 20.1 Liu TY, Ibrahim M, Bittencourt M, et al. Retinal optical coherence tomography manifestations of intraocular lymphoma. J Ophthal Inflamm Infect 2012; 2: 215-218.
↑ Chan CC. Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 2003;101:269-286
↑ Pulido JS, Salomão DR, Frederick LA, Viswanatha DS. MyD-88 L265P mutations are present in some cases of vitreoretinal lymphoma. Retina 2015;35(4):624-627
↑ Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93‐100.
↑ Kimura K, Usui Y, Goto H, et al. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 2012; 56: 383-389.
↑ Wang Y, Shen D, Wang VM, Sen HN, Chan CC. Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 2011;12:5684‐97.
↑ Buggage RR, Whitcup SM, Nussenblatt RB, Chan CC. Using interleukin 10 to interleukin 6 ratio to distinguish primary intraocular lymphoma and uveitis. Invest Ophthalmol Vis Sci 1999;40:2462-2463
↑ Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lympoma: A report from an international primary central nervous system lymphoma collaborative group symposium. The Oncologist. 2011;16: 1589-1599
↑ Berenbom A, Davila RM, Lin HS et al .Treatment outcomes for primary intra ocular lymphoma: implications for external beam radiotherapy. Eye 21: 1198-1201
↑ Isobe K, Ejima Y, Tokumaru S et al. Treatment of primary intraocular lymphoma with radiation therapy : a multi institutional survey in Japan . Leuk Lymphoma 47: 1800-1805
↑ De Smet MD, Vancs VS, Kohler D et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol 83: 448-451
↑ Frenkel S, Hendler K, Siegal T et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10years of experience . Br J Ophthalmol 92: 383-388
↑ Kitzmann AS, Pulido JS, Mohney BG. Intraocular use of rituximab. Eye. 2007; 21: 1524-1527.
↑ Pulido, J.S., Johnston, P.B., Nowakowski, G.S. et al. The diagnosis and treatment of primary vitreoretinal lymphoma: a review. Int J Retin Vitr 4, 18 (2018).
↑ Venkatesh R, Bavaharan B, Mahendradas P, Yadav NK. Primary vitreoretinal lymphoma: prevalence, impact, and management challenges. Clin Ophthalmol. 2019 Feb 14;13:353-364.
↑ 35.0 35.1 Kalogeropoulos D, Vartholomatos G, Mitra A, Elaraoud I, Ch'ng SW, Zikou A, Papoudou-Bai A, Moschos MM, Kanavaros P, Kalogeropoulos C. Primary vitreoretinal lymphoma. Saudi J Ophthalmol. 2019 Jan-Mar;33(1):66-80.
↑ Grimm S.A., Pulido J.S., Jahnke K. Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group report. Ann Oncol. 2007;18:1851–1855.
Oncology/Pathology
Retina/Vitreous

Diagnosis & Treatment of Intraocular Lymphoma

A look at the distinct clinical features that help to establish the diagnosis and guide treatment of these malignancies., related articles, infection: the evolving role of antibiotics, how to manage intraocular lymphoma, managing recurrent wet amd after treat & extend, the gut microbiome’s impact on the retina, treating endogenous endophthalmitis, current issue.

Read digital edition, read pdf edition, subscriptions.

For Ophthalmologists
For Practice Management
For Clinical Teams
For Public & Patients

Museum of the Eye

Latest Issue
Back Issues (Nov. 2012 to present)
Archive Highlights (pre Oct. 2012)
Dr. Richard Mills' Opinions, 2002 to 2016
Write For Us
Corporate Webinars
EyeNet Magazine
/ December 2015
/ Primary Vitreoretinal Lymphoma

Primary Vitreoretinal Lymphoma

Mark Complete

Download PDF

Primary vitreoretinal lymphoma (PVRL) has many names, including primary intraocular lymphoma or intraocular reticulum cell sarcoma, and it is a manifestation of primary central nervous system lymphoma (PCNSL). PVRL is a masquerade syndrome mimicking, for example, chronic uveitis; and its rarity, as well as the need for invasive diagnostic techniques, may delay diagnosis for up to 21 months after presentation. 1 The poor systemic prognosis for this condition makes it essential to keep PVRL in the differential for chronic inflammatory conditions.

Epidemiology

PVRL is a rare non-Hodgkin lymphoma. The true incidence of intraocular lymphoma is unknown, but based on its co-occurrence in approximately 20% of patients with PCNSL, the estimated incidence is between 0.02 and 0.1/100,000 in the United States. 2 While it has no race predilection, PVRL typically affects women in their fifth to sixth decade.

Association With CNS Lymphoma

PVRL often occurs concurrently with central nervous system lymphoma (CNSL); in fact, up to 90% of patients presenting with PVRL will develop CNSL within 29 months. 3 Conversely, as many as 28% of patients with PCNSL have concurrent intraocular involvement. 4 The most common form of PVRL is a diffuse large B-cell type that expresses specific ligands, leading to preferential homing to the retinal pigment epithelium (RPE) from choroidal vasculature.

Clinical Presentation

The disease’s insidious onset coupled with vague complaints from patients with PVRL are among the factors that make early diagnosis difficult. The differential diagnosis is broad and includes other ocular lymphomas, non-lymphomatous neoplastic conditions, and non-neoplastic conditions of the retina ( Table 1 ).

Symptoms. Nonetheless, a variety of clinical observations aid in diagnosis of PVRL. Typically, the disease mimics a steroid-resistant chronic uveitis with associated vitritis. The most common ocular complaints reported by patients include blurred vision, painless loss of vision, floaters, red eye, and photophobia. If PVRL presents concurrently with CNSL, there may be behavioral changes and neurological findings such as hemiparesis and ataxia.

Signs. On exam, clinical signs may overlap with those of chronic posterior uveitis. Anterior chamber signs may include mild cells and flare, but more typically, these signs are absent.

Vitritis is common in PVRL and may manifest as an “aurora borealis” effect as cells gather along vitreal fibers, especially in the superior peripheral vitreous. 2 In addition, the vitreous cells in PVRL tend to be larger and less abundant than those found in typical vitritis. Although it is not common, the classic “leopard spot” collection of subretinal pigmented lesions that coalesce over time may appear on funduscopic examination. 2 Retinal whitening, as seen in viral retinitis, is not a hallmark of this disease. Rarely, PVRL may be associated with exudative retinal detachment, a fundus mass, or concurrent optic nerve swelling.

A patient who is 50 years or older with steroid-resistant uveitis or persistent vitritis, minimal fundus changes, and generally preserved visual acuity should raise suspicion for PVRL.

Imaging. Ophthalmic imaging studies, though not specific or diagnostic, may help validate clinical suspicion of the disease. Fluorescein and indocyanine green angiography may exhibit localized hypofluorescent spots from subretinal infiltrate or hyperfluorescent window defects. Features present in other posterior uveitic conditions are not commonly seen, including perivascular staining, vessel leakage, cystoid macular edema, or optic nerve swelling.

Fundus autofluorescence patterns are typically normal but may highlight clinically observed areas of brown “leopard spots” as bright hyperautofluorescence. Chronic changes to the RPE may instead produce focal areas of dark hypoautofluoresence.

New findings that have been identified on optical coherence tomography include cellular infiltrates in the vitreous, focal pockets of subretinal hyper-reflective material between the RPE and Bruch’s membrane, and small pockets of RPE detachments.

Ophthalmic ultrasound is helpful to demonstrate choroidal thickening and rule out intraocular or orbital mass lesions as seen in choroidal lymphoma.

Laboratory testing. Once PVRL is considered in the differential diagnosis, more common causes of ocular inflammation should be eliminated, and directed systemic laboratory testing is usually needed. Definitive diagnosis requires identification of malignant lymphoid cells in the eye.

When vitritis is the predominant clinical sign, diagnostic pars plana vitrectomy to obtain both undiluted and partially diluted vitreous specimens is preferable to aqueous fluid collection or bedside vitreous tap. If multifocal white subretinal deposits are seen with minimal vitreous cells, a diagnostic vitrectomy may be combined with full-thickness chorioretinal biopsy or needle aspiration of subretinal material. Repeat biopsies may be required.

In all cases, specimens must be processed immediately and preferably hand-delivered by the operating surgeon to the laboratory for prompt analysis. After careful discussion with the pathologist, the surgeon should be certain that testing facilities are available for cytopathology.

Although cytopathology is most sensitive for detecting abnormal lymphoid cells, biomolecular analyses are available to bolster the diagnosis of B-cell PVRL, including detectable CD20, CD79, and PAX5. In rare cases, T-celldominated lymphoma may reveal CD3 and CD8 markers. Flow cytometric analysis may identify clonal B-cell populations on the basis of cell surface markers. Further tests include immunohistochemistry and elevated IL-10 to IL-6 ratio greater than 1, but clinicians should be aware of the low sensitivity of this method of testing.

If the diagnosis is confirmed, a team approach with a medical oncologist trained in treatment of CNS lymphoma is recommended to help coordinate systemic testing, including neuroimaging and lumbar puncture.

Treatment and Prognosis

Management of PVRL remains controversial, but it generally employs a multimodal approach including systemic therapy, radiotherapy, and intravitreal chemotherapy monitored by an oncologist. Systemic high-dose methotrexate (MTX)-based chemotherapy is used to treat both ocular and CNS disease. Many clinicians favor systemic therapy even for apparently isolated ocular disease, out of concern that subclinical CNS disease may be present concurrently.

Local ocular therapy may be used as monotherapy or as part of a combination that includes external beam radiotherapy to both globes and intravitreal MTX and rituximab. 5 The involvement of both eyes does not preclude the use of local therapy, but systemic therapy should be considered.

Prognosis. Relapse rates for PVRL are variable depending on treatment and follow-up. Despite advances in treatment and diagnosis, prognosis for those with PVRL/PCNSL remains dismal, with progression-free survival around 1 year and overall survival under 3 years. Although ocular therapy alone can achieve local control, it has little effect on overall survival.

PVRL remains an elusive diagnosis, with vague signs and symptoms and difficult diagnostic confirmation. Appropriate suspicion of chronic, treatment-resistant uveitis can aid in earlier detection. Definitive diagnosis still requires the identification of lymphoma cells within the vitreous or retina. Although the prognosis is poor, newer treatment modalities have increased survival while helping limit visual and neurologic side effects.

___________________________

1 Whitcup SM et al. Ophthalmology. 1993;100(9):1399-1406.

2 Chan CC et al. Oncologist . 2011;16(11):1589-1599.

3 Coupland SE et al . Graefes Arch Clin Exp Ophthalmol. 2004;242(11):901-913.

4 Hong JT et al. J Neurooncol . 2011;102(1):139-145.

5 Fishburne BC et al. Arch Ophthalmol. 1997;115(9):1152-1156.

Mr. Raufi is a fourth-year medical student at Albany Medical College, in Albany, N.Y. Dr. Cummings is professor of pathology at Duke Medical Center, Durham, N.C. Dr. Mruthyunjaya is a vitreoretinal surgeon who is director of the Duke Center for Ophthalmic Oncology at the Duke Eye Center. Relevant financial disclosures: None.

All content on the Academy’s website is protected by copyright law and the Terms of Service . This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.

About the Academy
Jobs at the Academy
Financial Relationships with Industry
Medical Disclaimer
Privacy Policy
Terms of Service
Statement on Artificial Intelligence
For Advertisers
Ophthalmology Job Center

FOLLOW THE ACADEMY

Medical Professionals

Public & Patients

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

View all journals
Explore content
About the journal
Publish with us
Sign up for alerts
Cambridge Ophthalmological Symposium
Published: 30 November 2012

Intraocular lymphoma: a clinical perspective

J L Davis 1

Eye volume 27 , pages 153–162 ( 2013 ) Cite this article

5784 Accesses

92 Citations

Metrics details

Cancer therapy
Pathogenesis

Primary vitreoretinal lymphoma (PVRL) is a rare malignancy that is speculated to arise extraocularly, and preferentially invade and flourish in the ocular and CNS microenvironments. The eye is involved in about 20% of primary central nervous system lymphomas, but the brain is eventually involved in about 80% of PVRL. Most are B-cell lymphomas with small numbers of T-cell lymphomas metastatic to the vitreous and retina. Metastatic systemic B-cell lymphoma usually involves choroid. Primary choroidal lymphoma is rare. Intraocular lymphoma can usually be distinguished from uveitis clinically, although there are overlaps, which may be pronounced in eyes with a large component of reactive inflammation related to tumor surveillance and control. There are controversies in diagnosis and treatment. Diagnosis through examination of ocular fluid is technically difficult and can utilize cytology, immunohistochemistry, flow cytometry, molecular detection of gene rearrangements, and cytokine profiling. Treatment of intraocular lymphoma without detectable CNS disease could consist of a full course of systemic chemotherapy with ocular adjunctive treatment, or ocular treatment alone depending on the preference of the clinical center. In ocular only cases where the vitreous has been debulked to improve vision and there is no sight-threatening involvement of the RPE, orbital irradiation or intravitreal chemotherapy stabilizes the intraocular process but does not seem to modify the CNS component, which can present symptomatically in an advanced state. This is a highly malignant disease with a poor prognosis. Close collaboration with a pathologist and oncologist, and good communication with patients is essential.

Methodology

Online search of the Medline database through August 2012 captured information regarding the epidemiology and clinical behavior of intraocular lymphomas using keywords of intraocular lymphoma, primary vitreoretinal lymphoma, metastatic intraocular lymphoma, and choroidal lymphoma. Search for lymphoma and vitreous captured articles on animal models and diagnostic testing. Searches under lymphoma and either methotrexate or rituximab revealed studies of treatment. Recent consensus documents from the United Kingdom and United States provided current practices in treatment.

Lymphoma is a rare form of intraocular malignancy, probably accounting for <0.01% of ophthalmic diseases. 1 , 2 The majority of patients are older than 50. Most intraocular lymphoma is a primary vitreoretinal lymphoma (PVRL) that involves the retinal pigment epithelium and vitreous, rather than the uvea as do secondary lymphomas such as metastatic systemic lymphoma. 2 , 3 , 4 Metastases of systemic lymphoma to the retina is extremely rare. 5 PVRL is closely associated with primary central nervous system lymphoma (PCNSL) to the extent that most cases presenting with ocular involvement will eventually develop CNS lymphoma. 1 , 2 Primary choroidal lymphoma represents another distinct form of intraocular lymphoma. 6

Diagnosis is considered difficult. Clinically lymphoma masquerades as an intermediate and/or posterior uveitis. Acquisition and preservation of vitreous specimens is technically challenging, 7 and few cytopathologists in general hospitals will have experience with this tumor. For this reason a number of adjunctive diagnostic tests have been devised to supplement cytology: immunohistochemistry, 8 flow cytometry, 9 molecular detection of clonal gene rearrangements, 10 , 11 and cytokine profiling of intraocular fluid. 10 , 11 , 12

Treatment is controversial in the absence of concurrent CNS disease. Systemic chemotherapy with a regimen including high-dose methotrexate plus an adjuvant local ocular therapy such as radiation is advocated by some. 13 , 14 Intraocular chemotherapy with methotrexate is preferred to radiation in some centers. 15 Rituximab shows some potential as another local adjuvant that may be less toxic than methotrexate 16 or avoid the develop of methotrexate resistance with repeated exposure. 17 Combined systemic and radiotherapy treatment is proposed to lengthen the survival time from the onset of ocular symptoms in patients who present with ocular involvement only. 18 Palliative local therapy may be prescribed if prophylactic systemic treatment is not elected. 2 Local therapy alone does not seem to modify overall prognosis. 19

The role of the ophthalmologist is to suspect the diagnosis, obtain adequate material for pathological examination, and to work closely with a pathologist to confirm the diagnosis and with an hemato-oncologist to participate in a treatment plan that considers both ocular and non-ocular involvement.

Clinical correlations with the pathogenesis of PVRL

Current scientific understanding of intraocular lymphoma supports the hypothesis of an infiltration of malignant lymphocytes from the systemic circulation to the eye and the brain. 3 Cells with clonal DNA rearrangements identical to those in the brain tumor have been found in the blood and bone marrow of patients with PCNSL. 20 Permissive retinal endothelial receptors 21 and lack of a robust immune surveillance may allow preferential entry of malignant cells to the retina rather than choroid, and subsequent clonal proliferation in the eye. Migration into vitreous or RPE or both occurs, with Bruchs membrane serving as a barrier to further spread. In contrast to PVRL, the choroidal circulation is the more likely entry point in metastatic systemic lymphoma. Bruchs membrane again acts as a barrier and confines the tumor to the uveal tract. Metastatic uveal infiltration in the iris is also possible but extremely rare. 3 , 22

Other mechanisms of lymphoma entry into the eye have been proposed. Because of the strong association of PCNSL with vitreoretinal lymphoma, passage along the optic nerves would be a convenient explanation; however, clinically the optic nerve is uninvolved in concurrent disease, unlike murine models of intraocular lymphoma. 23 Cases of infectious uveitis associated with subsequent intraocular lymphoma 24 could support a hypothesis of an initial polyclonal inflammatory proliferation that becomes clonal through mutation. Endoantigens from a non-infectious uveitis hypothetically might produce the same phenomenon. There is evidence that intraocular lymphoma arises from post-germinal center cells that have already been exposed to antigen. 25 In addition, ocular inflammation might supply growth factors for tumor cells rather than killing them.

Primary choroidal lymphoma is distinct from other forms of intraocular lymphoma, usually has a benign behavior with virtually no metastatic potential, but does locally proliferate and can damage the eye. 3 Most cases of reactive lymphoid hyperplasia are felt to be low-grade B-cell lymphomas that involve the choroid. 26

Table 1 summarizes recent basic and animal research with potential applications to the clinical understanding and management of intraocular lymphoma.

Clinical features of PVRL

The distinctive feature of homogeneous, non-clumped collections of large vitreous cells correlates with the intravitreal clonal proliferation of cells. Migration to the retinal pigment epithelium leads to characteristic yellow lesions of various sizes. Solid detachments of the RPE with irregular yellow deposits are considered pathognomonic of PVRL ( Figure 1 ).

Depiction of typical growth patterns for PVRL. Left, primarily vitreous infiltration. Vitreous haze was dense enough in some areas to completely obscure the fundus; the central clear zone permitted good vision of 20/30. Vitreous stranding and clumping typical of inflammatory disease is absent. Right, large deposit under the retinal pigment epithelium in an HIV-infected patient with PCNSL. The preretinal white patch on the dome of the lesion is lymphomatous proliferation into the vitreous. Note the vascular sheathing and the small clumps of RPE over the tumor mass.

Intraocular lymphoma can be distinguished clinically from uveitis based on two principal features. The first is that the lymphoma cells increase by a proliferation in situ rather than by the amplification and recruitment of inflammatory cells that occurs in uveitis. The second feature is that in B-cell PVRL there is predominance of IL-10 cytokine, 12 presumably elaborated by the lymphoma cells. It acts as a growth factor for B lymphocytes, along with other mediators, 36 and is also anti-inflammatory. This may stifle immune defenses against the tumor cells and produce the typical ‘quiet’ eye of PVRL. In contrast the inflammatory milieu in uveitis 37 with high levels of IL-6 is associated with breakdown of vitreous structure with stranding and focal vitreous opacities.

There are exceptions to these stereotypical patterns that can complicate clinical diagnosis. Higher degrees of reactive inflammation may occur when there are more reactive T-cell lymphocytes. Iritis and keratic precipitates occurred in about 25% of the 217 patients with intraocular lymphoma reported by the Japanese collaborative group 10 vs about 75% of 53 French patients. 38 Subretinal deposits were present in about half the patients in each group. 10 , 38 The most useful signs for distinguishing lymphoma from non-lymphoma patients in the French study of diagnostic vitrectomies were better vision, less anterior chamber flare, fewer cases with posterior synechiae, and less optic disc swelling, epiretinal membrane, or retinal vasculitis. 38

Imaging is becoming increasingly useful in diagnosis of PVRL. The RPE over yellow cellular accumulations of lymphoma cells is hyperautofluorescent, presumably due to RPE dysfunction with accumulation of fluorophores. The whiter retinal deposits over the RPE are hypoautofluorescent due to blocking 39 ( Figure 2 ).

Retinal lymphoma in a patient treated for PCNSL 5 years previously. Top left, right fundus photograph shows pale, round lesions. Top right, autofluorescent imaging shows the round lesions to be mainly hypofluorescent. The clustering of the lesions along retinal arterioles is better seen in the autofluorescent image and suggests entry into the eye via the retinal circulation. The optic nerve was normal. The diffuse hyperautofluorescence likely indicates RPE level infiltration. Bottom, video and spectral domain OCT through two of the round lesions confirms their intraretinal location. The lesion on the right has eroded through retina and is resting on the RPE.

Fluorescein angiography shows early and late hypofluorescent lesions in cases with outer retinal involvement ( Figure 3 ). 38 Focal deposits are minimal on indocyanine green angiography consistent with the predilection for the retinal rather than the uveal compartment. Irregular hyper-reflective anterior protrusions from the RPE on spectral domain OCT ( Figure 4 ) probably indicate deposits of cells at this preferential site. 38

RPE involvement in PVRL. Left, grayscale rendition of a color photograph. The pale lesions are lymphomatous deposits that appear yellow clinically. The larger round lesions are growing the RPE as evidenced by the clumps of pigment on their domes. The smaller punctate and spiculated deposits are also likely sub-RPE. Notice the hazy retinal infiltrates temporally in this right eye and the obscuration of the retinal vessels in this area either from sheathing or retinal infiltration. Right, early stage fluorescein angiogram of the same eye demonstrating classic leopard spot pigmentation. The hypofluorescent lesions are the deposits of lymphoma cells.

Autofluorescence and OCT imaging in PVRL. Left, the fundus is studded with multiple punctate hyperfluorescent dots. There is one placoid lesion in the inferior macula. The dark dots may represent areas of damage to the RPE or collections of lymphoma cells that have grown above the RPE and are blocking the native autofluorescence. Right, correlation with the OCT section through the fovea where the white dots are minimal nonetheless OCT shows multiple pre-Bruchs/sub-RPE deposits that protrude anteriorally to the outer retina.

Leakage of fluorescein along the retinal veins in PVRL was detected in 7 of 53 cases (13.2%) in the largest series of imaging to date. 38 Periarteriolar staining also occurs in lymphoma. When compared with non-lymphoma patients undergoing vitreous biopsy, vascular leakage is less common. 38 This sign of reactive inflammation seems likely to be relevant for the clinical behavior of PVRL but correlations between inflammatory signs such as vasculitis and tumor control have not been made.

Table 2 summarizes the ophthalmologic features useful in the clinical diagnosis of intraocular lymphoma. Early diagnosis may identify more cases with vitreous involvement only that will develop clinically evident RPE involvement at a later stage.

Diagnosis of intraocular lymphoma

If the diagnosis is suspected, lengthy testing for CNS disease in neurologically asymptomatic patients before ocular biopsy is not necessary. Positive results from a vitreous biopsy can help justify a full oncologic work-up rather than a simple MRI of the brain with contrast to make sure there is no obvious CNS disease. Nonetheless, once the diagnosis has been suspected, most ophthalmologists will feel uncomfortable following the patient unless the MRI is normal especially if biopsy results are inconclusive.

Cassoux et al 12 have proposed using anterior chamber tap for IL-10 determination as a screening test to determine whether vitreous biopsy is indicated. A cutoff value of 50 pg/ml IL-10 in aqueous humor yielded 0.89 sensitivity and 0.93 specificity for lymphoma in a series of 51 lymphoma patients and 108 uveitis controls. 12 Sensitivity of 0.8 and specificity of 0.99 were achieved with a cutoff value of 400 pg/ml IL-10 in vitreous humor in the same series. Mochizuki and colleagues 41 replicated their work in a case–control study using the IL-10 : IL-6 ratio as a diagnostic rather than screening test in which vitreous IL-10 levels >100 pg/ml and an IL-10 : IL-6 ratio of >1 were considered positive for lymphoma. The sensitivity, specificity, positive predictive value, and negative predictive value in this study were 0.818, 1.000, 1.000, and 0.714, respectively, indicating that a negative IL-10 assay does not exclude lymphoma. 41 An IL-10 : IL-6 ratio >1 was reported in 53 of 60 lymphoma patients (88%) by Chan and colleagues. 11 A collaborative Japanese study among 25 ophthalmology departments confirmed an IL-10 : IL-6 ratio of >1 in 133 of 145 patients (91.7%) with intraocular lymphoma. 10

Oncologists generally require cytologic evidence of malignant lymphocytes on vitreous biopsy before ocular treatment. The classic description is atypical lymphoid cells with large irregular nuclei, scanty cytoplasm, and prominent nucleoli. 2 , 3 Although the appearance of the cells is straightforward, cytologic diagnosis remains challenging. For example, the large Japanese study cited above had positive cytologic diagnoses in only 73 of 164 (44.5%) patients. 10 Cells recovered often seem far fewer than predicted based on the presurgical ophthalmoscopy. Some of the intraocular cells may be dead or damaged in transit or have poor cytomorphology. Direct aspiration through 21-gauge large bore needles, 42 and vitrectomy with 20-gauge vitrectors 9 or 25-gauge vitrectors 43 produces adequate specimens for morphologic diagnosis. Rapid processing within 1 h after acquisition has been recommended. 3 If transport is required to a remote pathology unit, transport medium may help preserve cellular morphology. 3 , 44 Consultation with the pathologist in advance of sending the specimen is highly recommended.

Immunohistochemical staining of cytologic slides is useful to enhance detection of B-cell lymphomas. 2 , 3 , 8 Typically, the selected stains are CD20, a B-cell marker; and kappa and lambda light chains. The strategy fails in intraocular T-cell lymphomas (which are rare) and in B-cell lymphomas that are too poorly differentiated to express CD20 or light chains on the cell surface. 45 In addition, large numbers of reactive T cells may obscure the malignant B-cell component. 45

Flow cytometry permits the use of larger numbers of cell surface markers and a more complete profiling of the cell surface markers of the intraocular cells. 9 , 45 , 46 , 47 For example, most diffuse large B-cell intraocular lymphomas do not express CD10, which distinguishes them from extramarginal zone lymphomas (MALT lymphomas), which typically affect the ocular adnexae rather than the intraocular compartment. 47 Inclusion of more cell surface markers, especially T-cell markers and activation markers, helps differentiate uveitis from lymphoma. This is especially true for the CD4 : CD8 ratio, which is elevated in vitreous from uveitis patients. 9 , 45 Kojima et al 48 reported significantly higher CD4 : CD8 ratios in vitreous than in blood among sarcoid uveitis patients and also significantly higher CD4 : CD8 ratios compared with patients with other types of uveitis.

A typical vitreous flow cytometric panel includes a general leukocyte marker CD45; T-cell markers CD2, CD3, CD4, CD5, CD7, CD8; B-cell markers CD19, CD20, CD22; kappa and lambda light-chain markers; CD10; CD14 macrophage/monocyte lineage; and HLA-DR, CD25, CD69 activation markers. A ratio of kappa : lambda of >3 or <0.6 is useful as a marker for clonality as the usual ratio in heterogeneous inflammatory reactions is close to 1. 9 There are drawbacks to this technique. Flow cytometry displays a statistical distribution of cell types that is more accurate with larger numbers of cells than can be obtained with vitrectomy. In addition, an expert operator is required to gate the cells to produce meaningful displays. 49

Flow cytometry has enabled the observation that cells with immunologic activation markers were common in vitreous specimens from B-cell lymphoma and T-cell lymphomas, as well as uveitis. 45 Statistical differences in the percentage of activated cells among these groups could not be demonstrated. In addition, abundant T cells were present in all three types of vitreous infiltrates, although they were present in statistically higher percentages in uveitis and T-cell lymphomas. 45 Reactive T cells in B-cell lymphoma were first recognized by Kennerdell et al 32 in 1975 and seem to be a protective mechanism although no clinical correlations have been drawn between ophthalmic presentations or prognosis, and increased reactive lymphocytes. Greater use of flow cytometry might permit enough data to be collected to make such correlations.

The observation that tumor infiltrating lymphocytes expanded in vitro to react with cutaneous melanoma antigens can enter the eye and produce a uveitis that resembles Vogt-Koyanagi-Harada is an example of at least one situation in which an immunologic tumor response produces a uveitis. 50 The implications is that one of the reasons that lymphoma may so often be confused with uveitis is that it is a uveitis as well in that it is a host reaction against tumor antigens inside the eye. Large numbers of reactive T cells can produce a phenotype of T-cell enriched B-cell lymphomas in the eye or brain. 33 , 51 Diagnosis is often markedly delayed in such cases because the expected B-cell phenotype is masked by inflammation. 33

Polymerase chain reaction (PCR) based assays detect a clonally expanded population of lymphocytes by demonstration of one or two identically sized PCR products after amplification and gel electrophoresis. 11 Primers target the complementarity defining regions of the variable region of the immunoglobulin heavy chain (IgH) or the T-cell receptor gamma (TCR). 52 In the case of B-cell lymphoma, the Japanese collaboration reported positive gene rearrangements in 54 of 67 patients (80.6%). 10 Only gene rearrangements in the immunoglobulin gene were performed. Chan and colleagues 11 found either IgH or TCR gene rearrangements in 100% of 114 intraocular lymphoma patients. Cells were collected by microdissection of abnormal lymphocytes from glass slides; sampling of too few cells could lead to a false-positive result. In Hochberg and colleagues 53 study of 17 patients, gene rearrangement had a higher sensitivity (0.64) for the detection of intraocular lymphoma than cytology or flow cytometry. A smaller study reported 6 of 7 samples of intraocular B-cell lymphoma with rearrangements of the kappa light chain. 45

A comprehensive review of diagnostic techniques and yields was published in 2007. 7 Yields of the various techniques in institutional series are difficult to compare because of biases introduced by clinical case selection. Multiple techniques are usually recommended. Table 3 summarizes the consensus recommendations of three panels of experts concerning diagnostic testing in intraocular and CNS lymphoma.

Randomized-controlled clinical trials have not been performed for PVRL and are unlikely. Published recommendations from the International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) symposium on PVRL 2 and from the British Neuro-Oncology Society (NCAT Rare Tumor Guidelines, June 2011, http://www.bnos.org.uk ) differ in recommendations for the management of PVRL without concomitant brain lymphoma. The IPCG symposium on PVRL specifies local treatment for uniocular disease and either local treatment only or systemic chemotherapy with local treatment for bilateral ocular disease, whereas the British guidelines specify systemic chemotherapy incorporating high-dose methotrexate with whole-globe irradiation for ocular only disease. Table 3 summarizes recommendations relevant to treatment of intraocular disease from these two groups and from a third consensus group composed of 21 cancer centers in the United States ( http://www.nccn.org ).

It is unclear if treatment of ocular only disease improves outcomes. In one retrospective study, 17 patients treated for ocular only disease with chemotherapy and/or irradiation lived an average of 60 months after onset of ocular symptoms until death compared with 35 months for 14 patients who were treated only after CNS disease developed. 18 Observations of treatment outcomes in 176 patients with PCNSL with ocular dissemination were collected retrospectively by the IPCG in 2008. 19 Seventy-nine were treated with ocular irradiation and 22 with intravitreal methotrexate. Ocular treatment extended the time to progression, but not survival time, and it did not reduce the risk of ocular recurrence.

Ocular irradiation carries risks of cataract formation, radiation retinopathy, or optic neuropathy but is the preferred ocular treatment in many centers. 13 , 54 Intravitreal chemotherapy with methotrexate 400 μ g in 0.1 ml in an intensive induction-consolidation-maintenance regimen of 25 injections delivered over 1 year is used to avoid radiation complications but carries risks of keratopathy and maculopathy, as well as drug resistance. 15 , 17 Claims of therapeutic superiority of radiation over intraocular chemotherapy have not been made. Fewer intravitreal injections 55 and more widely spaced injections 56 have been advocated to increase the acceptability of intraocular chemotherapy ( Figure 5 ). The BNOS guidelines limit intravitreal methotrexate to salvage therapy after failure of radiation therapy and systemic chemotherapy ( Table 3 ). Rituximab has been proposed as an alternative to methotrexate with the idea that it may be a less toxic alternative. 16

Initial response to intravitreal methotrexate in a patient with PVRL who has not received prior treatment with corticosteroids, systemic chemotherapy, or ocular irradiation. Left, a large retinal infiltrate developed in a patient status post diagnostic vitrectomy showing B-cell predominance on flow cytometry but untreated by the hemato-oncologic consultant. Top right, spectral domain OCT through the infiltrated area on the day of injection (baseline). There are heavy deposits under the RPE and retina. The segmentation line is improperly drawn: Bruch’s membrane corresponds to the smooth white line just anterior to the choroidal vessels. Bottom right, spectral domain OCT 2-weeks after intravitreal methotrexate injection 400 μ g in 0.1 ml. There is dramatic resolution of the cellular deposits. The gray segmentation line is properly drawn along Bruch’s membrane. Overall thickness is markedly reduced.

Treatment of ocular only disease is likely complicated by presentation to vitreoretinal specialists or uveitis specialists rather than to ocular oncologists. PVRL patients are less likely to be presented to Tumor Boards and the relationship between the ophthalmologist and the oncologist is often a new one. Excellent communication and description of ocular findings and the results of tests on ocular fluid is helpful but most oncologists are reluctant to treat systemically without cytologic evidence of malignant disease. The ophthalmologist could apply intravitreal therapy or refer directly to the radiotherapist. In both cases continued observation and comanagement with the oncologist or neuro-oncologist is advised because of the high likelihood of eventual CNS disease.

Future directions

Advances in PVRL will rely on translational research to bridge gaps in diagnosis and treatment. 57 Management of intraocular lymphoma is already highly invested in molecular strategies such as PCR detection of monoclonality, characterization of cell surface markers and cytokine profiling. 11 Further extensive molecular characterization of tumor cells from individual patients may help elucidate pathogenesis and predict clinical behavior. 58 Improved chemotherapeutic regimens incorporating systemic rituximab and cytarabine may improve the prognosis of brain lymphoma. 59 Confirmation that PVRL is a manifestation of an occult, multicentric lymphoma would lead to aggressive systemic treatment for ocular only cases presenting without obvious CNS disease.

Mochizuki M, Singh AD . Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm 2009; 17 : 69–72.

Article Google Scholar

Chan CC, Rubenstein JL, Coupland SE, Davis JL, Harbour JW, Johnston PB et al . Primary vitreoretinal lymphoma: a report from an international primary central nervous system lymphoma collaborative group symposium. Oncologist 2011; 16 : 1589–1599.

Coupland SE, Damato B . Understanding intraocular lymphomas. Clin Experiment Ophthalmol 2008; 36 : 564–578.

Coupland SE, Foss HD, Hidayat AA, Cockerham GC, Hummel M, Stein H . Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases. J Pathol 2002; 197 : 333–340.

Cao X, Shen D, Callanan DG, Mochizuki M, Chan CC . Diagnosis of systemic metastatic retinal lymphoma. Acta Ophthalmol 2011; 89 : e149–e154.

Coupland SE, Heimann H, Bechrakis NE . Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features. Graefes Arch Clin Exp Ophthalmol 2004; 242 : 901–913.

Gonzales JA, Chan CC . Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 2007; 27 : 241–250.

Davis JL, Solomon D, Nussenblatt RB, Palestine AG, Chan CC . Immunocytochemical staining of vitreous cells. Indicat Tech Result Ophthalmol 1992; 99 : 250–256.

CAS Google Scholar

Davis JL, Miller DM, Ruiz P . Diagnostic testing of vitrectomy specimens. Am J Ophthalmol 2005; 140 : 822–829.

Kimura K, Usui Y, Goto H, The Japanese Intraocular Lymphoma Study Group. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 2012; 56 : 383–389.

Wang Y, Shen D, Wang VM, Sen HN, Chan CC . Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 2011; 12 : 5684–5697.

Article CAS Google Scholar

Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F et al . IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2007; 48 : 3253–3259.

Berenbom A, Davila RM, Lin HS, Harbour JW . Treatment outcomes for primary intraocular lymphoma: implications for external beam radiotherapy. Eye 2007; 21 : 1198–1201.

Stefanovic A, Davis J, Murray T, Markoe A, Lossos IS . Treatment of isolated primary intraocular lymphoma with high-dose methotrexate-based chemotherapy and binocular radiation therapy: a single-institution experience. Br J Haematol 2010; 151 : 103–106.

Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J . Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol 2008; 92 : 383–388.

Itty S, Pulido JS . Rituximab for intraocular lymphoma. Retina 2009; 29 : 129–132.

Sen HN, Chan CC, Byrnes G, Fariss RN, Nussenblatt RB, Buggage RR . Intravitreal methotrexate resistance in a patient with primary intraocular lymphoma. Ocul Immunol Inflamm 2008; 16 : 29–33.

Hormigo A, Abrey L, Heinemann MH, DeAngelis LM . Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol 2004; 126 : 202–208.

Grimm SA, McCannel CA, Omuro AM, Ferreri AJ, Blay JY, Neuwelt EA et al . Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group report. Neurology 2008; 71 : 1355–1360.

McCann KJ, Ashton-Key M, Smith K, Stevenson FK, Ottensmeier CH . Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence for separate development. Blood 2009; 113 : 4677–4688.

Zamora DO, Rivere M, Choi D, Pan Y, Planck SR, Rosenbaum JR et al . Proteomic profiling of human retinal and choroidal endothelial cells reveals molecular heterogeneity related to tissue of origin. Mol Vis 2007; 13 : 2058–2065.

CAS PubMed Google Scholar

Velez G, de Smet MD, Whitcup SM, Robinson M, Nussenblatt RB, Chan CC . Iris involvement in primary intraocular lymphoma: report of two cases and review of the literature. Surv Ophthalmol 2000; 44 : 518–526.

Chan CC, Fischette M, Shen D, Mahesh SP, Nussenblatt RB, Hochman J . Murine model of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2005; 46 : 415–419.

Sauer TC, Meyers SM, Shen D, Vegh S, Vygantas C, Chan CC . Primary intraocular (retinal) lymphoma following ocular toxoplasmosis. Retin Cases Brief Rep 2010; 4 : 160–163.

Malumbres R, Davis J, Ruiz P, Lossos IS . Somatically mutated immunoglobulin IGHV@ genes without intraclonal heterogeneity indicate a postgerminal centre origin of primary intraocular diffuse large B-cell lymphomas. Br J Haematol 2007; 138 : 749–755.

Cockerham GC, Hidayat AA, Bijwaard KE, Sheng ZM . Re-evaluation of ‘reactive lymphoid hyperplasia of the uvea’: an immunohistochemical and molecular analysis of 10 cases. Ophthalmology 2000; 107 : 151–158.

Mineo JF, Scheffer A, Karkoutly C, Nouvel L, Kerdraon O, Trauet J et al . Using human CD20-transfected murine lymphomatous B cells to evaluate the efficacy of intravitreal and intracerebral rituximab injections in mice. Invest Ophthalmol Vis Sci 2008; 49 : 4738–4745.

Chan CC, Shen D, Hackett JJ, Buggage RR, Tuaillon N . Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma. Ophthalmology 2003; 110 : 421–426.

Galand C, Donnou S, Crozet L, Brunet S, Touitou V, Ouakrim H et al . Th17 cells are involved in the local control of tumor progression in primary intraocular lymphoma. PLoS One 2011; 6 : e24622.

Kitzmann AS, Pulido JS, Mohney BG, Baratz KH, Grube T, Marler RJ et al . Intraocular use of rituximab. Eye (Lond) 2007; 21 : 1524–1527.

Turaka K, Bryan JS, De Souza S, Gordon AJ, Kwong HM, Ziemianski MC et al . Vitreoretinal lymphoma: changing trends in diagnosis and local treatment modalities at a single institution. Clin Lymphoma Myeloma Leuk 2012; S2152-2650 (12): 00141–00143.

Google Scholar

Kennerdell JS, Johnson BL, Wisotzkey HM . Vitreous cellular reaction. Association with reticulum cell sarcoma of brain. Arch Ophthalmol 1975; 93 : 1341–1345.

Cummings TJ, Stenzel TT, Klintworth G, Jaffe GJ . Primary intraocular T-cell-rich large B-cell lymphoma. Arch Pathol Lab Med 2005; 129 : 1050–1053.

PubMed Google Scholar

Forsyth PA, DeAngelis LM . Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am 1996; 10 : 1125–1134.

Thomas JA, Crawford DH, Burke M . Clinico-pathologic implications of Epstein-Barr virus related B cell lymphoma in immunocompromised patients. J Clin Pathol 1995; 48 : 287–290.

Usui Y, Wakabayashi Y, Okunuki Y, Kimura K, Tajima K, Matsuda R et al . Immune mediators in vitreous fluids from patients with vitreoretinal B-cell lymphoma. Invest Ophthalmol Vis Sci 2012; 53 : 5395–5402.

Valentincic NV, de Groot-Mijnes JD, Kraut A, Korosec P, Hawlina M, Rothova A . Intraocular and serum cytokine profiles in patients with intermediate uveitis. Mol Vis 2011; 17 : 2003–2010.

CAS PubMed PubMed Central Google Scholar

Fardeau C, Lee CP, Merle-Béral H, Cassoux N, Bodaghi B, Davi F et al . Retinal fluorescein, indocyanine green angiography, and optic coherence tomography in non-Hodgkin primary intraocular lymphoma. Am J Ophthalmol 2009; 147 : 886–894.

Ishida T, Ohno-Matsui K, Kaneko Y, Tobita H, Shimada N, Takase H et al . Fundus autofluorescence patterns in eyes with primary intraocular lymphoma. Retina 2010; 30 : 23–32.

Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140 : 509–516.

Sugita S, Takase H, Sugamoto Y, Arai A, Miura O, Mochizuki M . Diagnosis of intraocular lymphoma by polymerase chain reaction analysis and cytokine profiling of the vitreous fluid. Jpn J Ophthalmol 2009; 53 : 209–214.

Lobo A, Lightman S . Vitreous aspiration needle tap in the diagnosis of intraocular inflammation. Ophthalmology 2003; 110 : 595–599.

Yeh S, Weichel ED, Faia LJ, Albini TA, Wroblewski KK, Stetler-Stevenson M et al . 25-Gauge transconjunctival sutureless vitrectomy for the diagnosis of intraocular lymphoma. Br J Ophthalmol 2010; 94 : 633–638.

Coupland SE, Perez-Canto A, Hummel M, Stein H, Heimann H . Assessment of HOPE fixation in vitrectomy specimens in patients with chronic bilateral uveitis (masquerade syndrome). Graefes Arch Clin Exp Ophthalmol 2005; 243 : 847–852.

Davis JL, Ruiz P, Shah M, Mandelcorn E . Evaluation of the reactive t cell infiltrate in uveitis and intraocular lymphoma with flow cytometry of vitreous fluid. An AOS thesis. Trans Am Ophth Soc 2012 (in press).

Zaldivar RA, Martin DF, Holden JT, Grossniklaus HE . Primary intraocular lymphoma: clinical, cytologic, and flow cytometric analysis. Ophthalmology 2004; 111 : 1762–1767.

Raparia K, Chang CC, Chévez-Barrios P . Intraocular lymphoma: diagnostic approach and immunophenotypic findings in vitrectomy specimens. Arch Pathol Lab Med 2009; 133 : 1233–1237.

Kojima K, Maruyama K, Inaba T, Nagata K, Yasuhara T, Yoneda K et al . The CD4/CD8 Ratio in vitreous fluid is of high diagnostic value in sarcoidosis. Ophthalmology 2012; 119 (11): 2386–2392.

Lugli E, Roederer M, Cossarizza A . Data analysis in flow cytometry: the future just started. Cytometry A 2010; 77 : 705–713.

Yeh S, Karne NK, Kerkar SP, Heller CK, Palmer DC, Johnson LA et al . Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology 2009; 116 : 981–989.

Bashir R, Chamberlain M, Ruby E, Hochberg FH . T-cell infiltration of primary CNS lymphoma. Neurology 1996; 46 : 440–444.

Evans PA, Ch Pott, Groenen PJ, Salles G, Davi F, Berger F et al . Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007; 21 : 207–214.

Baehring JM, Androudi S, Longtine JJ, Betensky RA, Sklar J, Foster CS et al . Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma. Cancer 2005; 104 : 591–597.

Rajagopal R, Harbour JW . Diagnostic testing and treatment choices in primary vitreoretinal lymphoma. Retina 2011; 31 : 435–440.

Velez G, Boldt HC, Whitcup SM, Nussenblatt RB, Robinson MR . Local methotrexate and dexamethasone phosphate for the treatment of recurrent primary intraocular lymphoma. Ophthalmic Surg Lasers 2002; 33 : 329–333.

Helbig H, Cerny T, de Smet MD . [Intravitreal chemotherapy for intraocular lymphoma]. Ophthalmologe 2003; 100 : 145–149.

Chan CC, Fisson S, Bodaghi B . The future of primary intraocular lymphoma (retinal lymphoma). Ocul Immunol Inflamm 2009; 17 : 375–379.

Coupland SE, Hummel M, Müller HH, Stein H . Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 2005; 46 : 3507–3514.

Wieduwilt MJ, Valles F, Issa S, Behler CM, Hwang J, McDermott M et al . Immunochemotherapy with intensive consolidation for primary CNS lymphoma: a pilot study and prognostic assessment by diffusion-weighted MRI. Clin Cancer Res 2012; 18 : 1146–1155.

Download references

Acknowledgements

This research was supported by Len-Ari Foundation, Research to Prevent Blindness.

Author information

Authors and affiliations.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA

You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J L Davis .

Ethics declarations

Competing interests.

The authors declare no conflict of interest.

Additional information

Presented 14 September 2012 at the Cambridge Ophthalmological Symposium: cancer and the eye.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Davis, J. Intraocular lymphoma: a clinical perspective. Eye 27 , 153–162 (2013). https://doi.org/10.1038/eye.2012.250

Download citation

Received : 08 October 2012

Accepted : 09 October 2012

Published : 30 November 2012

Issue Date : February 2013

DOI : https://doi.org/10.1038/eye.2012.250

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

intraocular lymphoma
masquerade syndromes
primary vitreoretinal lymphoma
primary central nervous system lymphoma

This article is cited by

Diagnosis and management of vitreoretinal lymphoma: present and future treatment perspectives.

Toshikatsu Kaburaki
Kazuki Taoka

Japanese Journal of Ophthalmology (2023)

First observation of intraocular extranodal natural killer/T-cell lymphoma secondary to a retroperitoneal tumour: a case report and comparative review

Binyao Chen
Shizhao Yang

BMC Ophthalmology (2022)

Epidemiology and survival outcomes of patients with primary intraocular lymphoma: a population-based analysis

Lin-feng He
Jin-di Zhang

Clinical sign and symptom of primary vitreoretinal lymphoma short-time after retinal reattachment surgery: a case report

Marjan Imani Fooladi
Abdulrahim Amini
Fariba Ghassemi

Journal of Ophthalmic Inflammation and Infection (2022)

Quick links

Explore articles by subject
Guide to authors
Editorial policies

Primary Intraocular Lymphoma

pp 1467–1485

Cite this chapter

Chi-Chao Chan MD 6 ,
Sebastian P. Haen 7 ,
Robert Möhle 7 &
Manfred Zierhut MD 8

178 Accesses

4 Citations

Primary intraocular lymphoma (PIOL) is a neoplasm, most frequently of B-cell and rarely T-cell origin arising from or initially presenting in the eye. PIOL of the B-cell type is a non-Hodgkin’s lymphoma of the diffuse large B-cell type that belongs within the category of primary central nervous system lymphoma (PCNSL). The lymphoma always is located in the subretinal space, retina, vitreous, and/or optic nerve. Since the retina, retinal pigment epithelium (RPE), and optic nerve are derived from the same neuroectoderm as the CNS during embryogenesis, and both the eye and CNS are immune-privileged organs, PIOL is often considered to be a subtype of PCNSL. Although a subtype of PCNSL, PIOL may arise de novo in the neuroretina rather than secondary involvement from a PCNSL.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Available as PDF
Read on any device
Instant download
Own it forever
Available as EPUB and PDF
Durable hardcover edition
Dispatched in 3 to 5 business days
Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Chan CC, Gonzalez JA (2007) Primary intraocular lymphoma. Chennai World Scientific Publishing Co. Pte. Ltd., New Jersey

Book Google Scholar

Coupland SE, Anastassiou G, Bornfeld N, Hummel M, Stein H (2005) Primary intraocular lymphoma of T-cell type: report of a case and review of the literature. Graefes Arch Clin Exp Ophthalmol 243(3):189–197

Article PubMed Google Scholar

Hochberg FH, Baehring JM, Hochberg EP (2007) Primary CNS lymphoma. Nat Clin Pract Neurol 3(1):24–35

Article CAS PubMed Google Scholar

Chan CC, Rubenstwin JL, Coupland SE, Davis JL, Harbour JW, Johnston PB, Cassoux N, Touitou V, Smith JR, Batchelor TT, Pulido JS (2011) Primary vitreoretinal lymphoma: a report from an international primary central nervous system lymphoma collaborative group symposium. Oncologist 16:1589–1599

Article PubMed Central PubMed Google Scholar

Chan CC (2003) Molecular pathology of primary intraocular lymphoma. Trans Am Ophthalmol Soc 101:275–292

PubMed Central PubMed Google Scholar

Chan CC, Sen HN (2013) Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 15:93–100

Merle-Beral H, Davi F, Cassoux N, Baudet S, Colin C, Gourdet T et al (2004) Biological diagnosis of primary intraocular lymphoma. Br J Haematol 124:469–473

Coupland SE, Damato B (2006) Lymphomas involving the eye and the ocular adnexa. Curr Opin Ophthalmol 17:523–531

PubMed Google Scholar

Read RW, Zamir E, Rao NA (2002) Neoplastic masquerade syndromes. Surv Ophthalmol 47:81–124

Rothova A, Ooijman F, Kerkhoff F, Van Der Lelij A, Lokhorst HM (2001) Uveitis masquerade syndromes. Ophthalmology 108:386–399

Davis JL (2004) Diagnosis of intraocular lymphoma. Ocul Immunol Inflamm 12(1):7–16

Eby NL, Grufferman S, Flannelly CM, Schold SC Jr, Vogel FS, Burger PC (1988) Increasing incidence of primary brain lymphoma in the US. Cancer 62(11):2461–2465

Thomas JO (2001) Acquired immunodeficiency syndrome-associated cancers in Sub-Saharan Africa. Semin Oncol 28(2):198–206

Olson JE, Janney CA, Rao RD, Cerhan JR, Kurtin PJ, Schiff D et al (2002) The continuing increase in the incidence of primary central nervous system non-Hodgkin lymphoma: a surveillance, epidemiology, and end results analysis. Cancer 95(7):1504–1510

Chan CC, Buggage RR, Nussenblatt RB (2002) Intraocular lymphoma. Curr Opin Ophthalmol 13(6):411–418

Gupta R, Murray PI (2006) Chronic non-infectious uveitis in the elderly: epidemiology, pathophysiology and management. Drugs Aging 23(7):535–558

Kadoch C, Treseler P, Rubenstein JL (2006) Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 21(5):E1

Char DH, Ljung BM, Miller T, Phillips T (1988) Primary intraocular lymphoma (ocular reticulum cell sarcoma) diagnosis and management. Ophthalmology 95:625–630

Rockwood EJ, Zakov ZN, Bay JW (1984) Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). J Neurosurg 61:369–374

Hormigo A, Abrey L, Heinemann MH, DeAngelis LM (2004) Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol 126(2):202–208

Levy-Clarke GA, Chan CC, Nussenblatt RB (2005) Diagnosis and management of primary intraocular lymphoma. Hematol Oncol Clin North Am 19(4):739–749

Algazi AP, Kadoch C, Rubenstein JL (2009) Biology and treatment of primary central nervous system lymphoma. Am Soc Exp Neuro Ther Inc 6:587–597

CAS Google Scholar

Balmaceda C, Gaynor JJ, Sun M et al (1995) Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 38:202–209

Wallace DJ, Altemare CR, Shen DF, de Smet MD, Buggage RR, Nussenblatt RB, Chan CC (2006) Primary testicular and intraocular lymphomas: two case reports and a review of the literature. Surv Ophthalmol 51:41–50

Mochizuki M, Singh AD (2009) Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm 17:69–72

Peterson K, Gordon KB, Heinemann MH et al (1993) The clinical spectrum of ocular lymphoma. Cancer 72:843–849

Cassoux N, Merle-Beral H, Leblond V et al (2000) Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocul Immunol Inflamm 8:243–250

Wakefield D, Zierhut M (2009) Intraocular lymphoma: more questions than answers. Ocul Immunol Inflamm 17:6–10

Freeman LN, Schachat AP, Knox DL et al (1987) Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 94:1631–1639

Dean JM, Novak MA, Chan CC et al (1996) Tumor detachments of the retinal pigment epithelium in ocular/central nervous system lymphoma. Retina 16:47–56

Gass JD, Sever RJ, Grizzard WS et al (1984) Multifocal pigment epithelial detachments by reticulum cell sarcoma. A characteristic funduscopic picture. Retina 4:135–143

Gass JD, Trattler HL (1991) Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 109:1134–1139

Michelson JB, Michelson PE, Bordin GM et al (1981) Ocular reticulum cell sarcoma. Presentation as retinal detachment with demonstration of monoclonal immunoglobulin light chains on the vitreous cells. Arch Ophthalmol 99:1409–1411

Fine HA, Mayer RJ (1993) Primary central nervous system lymphoma. Ann Intern Med 119(11):1093–1104

Barr CC, Green WR, Payne JW, Knox DL, Jensen AD, Thompson RL (1975) Intraocular reticulum-cell sarcoma: clinico-pathologic study of four cases and review of the literature. Surv Ophthalmol 19(4):224–239

CAS PubMed Google Scholar

Whitcup SM, de Smet MD, Rubin BI, Palestine AG, Martin DF, Burnier MJ et al (1993) Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 100:1399–1406

Shibata S (1989) Sites of origin of primary intracerebral malignant lymphoma. Neurosurgery 25(1):14–19

Paulus W (1999) Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol 43(3):203–208

Hochberg FH, Miller DC (1988) Primary central nervous system lymphoma. J Neurosurg 68(6):835–853

Chan CC, Shen DF, Whitcup SM, Nussenblatt RB, LeHoang P, Roberge FG et al (1999) Detection of human herpesvirus-8 and Epstein-Barr virus DNA in primary intraocular lymphoma. Blood 93(8):2749–2751

Shen DF, Herbort CP, Tuaillon N, Buggage RR, Egwuagu CE, Chan CC (2001) Detection of toxoplasma gondii DNA in primary intraocular b-cell lymphoma. Mod Pathol 14(10):995–999

Buggage RR, Chan CC, Nussenblatt RB (2001) Ocular manifestations of central nervous system lymphoma. Curr Opin Oncol 13(3):137–142

Wang SS, Cozen W, Cerhan JR, Colt JS, Morton LM, Engels EA et al (2007) Immune mechanisms in non-Hodgkin lymphoma: joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors. Cancer Res 67(10):5042–5054

Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT et al (2006) Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7(1):27–38

Ramkumar HL, Shen DF, Tuo J, Braziel RM, Coupland SE, Smith JR, Chan CC (2012) IL-10–1082 SNP and IL-10 in primary CNS and vitreoretinal lymphoma. Graefe’s Arch Clin Exp Ophthalmol 250:1541–1548

Article CAS Google Scholar

Drillenburg P, Pals ST (2000) Cell adhesion receptors in lymphoma dissemination. Blood 95(6):1900–1910

Bashir R, Coakham H, Hochberg F (1992) Expression of LFA-1/ICAM-1 in CNS lymphomas: possible mechanism for lymphoma homing into the brain. J Neurooncol 12(2):103–110

Chan CC, Shen D, Hackett JJ, Buggage RR, Tuaillon N (2003) Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary intraocular lymphoma. Ophthalmology 110(2):421–426

Smith JR, Braziel RM, Paoletti S, Lipp M, Uguccioni M, Rosenbaum JT (2003) Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 101(3):815–821

Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769):503–511

Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI et al (2002) The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346(25):1937–1947

Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T et al (2006) Gene expression and angiotropism in primary CNS lymphoma. Blood 107(9):3716–3723

Article PubMed Central CAS PubMed Google Scholar

Tuaillon N, Chan CC (2001) Molecular analysis of primary central nervous system and primary intraocular lymphoma. Curr Mol Med 1(2):259–272

Coupland SE, Hummel M, Muller HH, Stein H (2005) Molecular analysis of immunoglobulin genes in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 46(10):3507–3514

Wallace DJ, Shen D, Reed GF, Miyanaga M, Mochizuki M, Sen HN et al (2006) Detection of the bcl-2 t(14;18) translocation and proto-oncogene expression in primary intraocular lymphoma. Invest Ophthalmol Vis Sci 47(7):2750–2756

Young LS, Murray PG (2003) Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22(33):5108–5121

Hochberg FH, Miller G, Schooley RT, Hirsch MS, Feorino P, Henle W (1983) Central-nervous-system lymphoma related to Epstein-Barr virus. N Engl J Med 309(13):745–748

Bashir RM, Harris NL, Hochberg FH, Singer RM (1989) Detection of Epstein-Barr virus in CNS lymphomas by in-situ hybridization. Neurology 39(6):813–817

Sauer TC, Meyers SM, Shen D, Vegh S, Vygantas C, Chan CC (2010) Primary intraocular (retinal) lymphoma following ocular toxoplasmosis. Retin Cases Brief Rep 4:160–163

Bolin TD, Hunt RH, Korman MG, Lambert JR, Lee A, Talley NJ (1995) Helicobacter pylori and gastric neoplasia: evolving concepts. Med J Aust 163(5):253–255

Chan CC, Shen D, Mochizuki M, Gonzales JA, Yuen HK, Guex-Crosier Y et al (2006) Detection of Helicobacter pylori and Chlamydia pneumoniae genes in primary. Trans Am Ophthalmol Soc 104:62–70

Smedby KE, Baecklund E, Askling J (2006) Malignant lymphomas in autoimmunity and inflammation: a review of risks. Cancer Epidemiol Biomarkers Prev 15(11):2069–2077

Smedby KE, Hjalgrim H, Askling J, Chang ET, Gregersen H, Porwit-MacDonald A et al (2006) Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin. J Natl Cancer Inst 98(1):51–60

Zintzaras E, Voulgarelis M, Moutsopoulos HM (2005) The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med 165(20):2337–2344

Parver LM, Font RL (1979) Malignant lymphoma of the retina and brain. Initial diagnosis by cytologic examination of vitreous aspirate. Arch Ophthalmol 97(8):1505–1507

Blumenkranz MS, Ward T, Murphy S, Mieler W, Williams GA, Long J (1992) Applications and limitations of vitreoretinal biopsy techniques in intraocular large cell lymphoma. Retina 12(3):S64–S70

Davis JL, Solomon D, Nussenblatt RB, Palestine AG, Chan CC (1992) Immunocytochemical staining of vitreous cells. Indications, techniques, and results. Ophthalmology 99(2):250–256

Wolf LA, Reed GF, Buggage RR, Nussenblatt RB, Chan CC (2003) Vitreous cytokine levels. Ophthalmology 110(8):1671–1672

Whitcup SM, Stark-Vancs V, Wittes RE, Solomon D, Podgor MJ, Nussenblatt RB et al (1997) Association of interleukin-10 in the vitreous and cerebral spinal fluid and primary central nervous system lymphoma. Arch Ophthalmol 115:1157–1160

Chan CC, Whitcup SM, Solomon D, Nussenblatt RB (1995) Interleukin-10 in the vitreous of primary intraocular lymphoma. Am J Ophthalmol 120(5):671–673

Benjamin D, Park CD, Sharma V (1994) Human B cell interleukin 10. Leuk Lymphoma 12(3–4):205–210

Blay JY, Burdin N, Rousset F, Lenoir G, Biron P, Philip T et al (1993) Serum interleukin-10 in non-Hodgkin’s lymphoma: a prognostic factor. Blood 82(7):2169–2174

Chan CC, Shen DF (1999) Newer methodologies in immunohistochemistry and diagnosis. In: BenEzra D (ed) Uveitis update. Karger, Basel, pp 1–13

Chapter Google Scholar

Salmaggi A, Eoli M, Corsini E, Gelati M, Frigerio S, Silvani A et al (2000) Cerebrospinal fluid interleukin-10 levels in primary central nervous. Ann Neurol 47(1):137–138

Cassoux N, Giron A, Bodaghi B, Tran TH, Baudet S, Davy F et al (2007) IL-10 measurement in aqueous humor for screening patients with suspicion of primary intraocular lymphoma. Invest Ophthalmol Vis Sci 48(7):3253–3259

Chan CC, Shen D, Nussenblatt RB, Boni R, Zhuang Z (1998) Detection of molecular changes in primary intraocular lymphoma by microdissection and polymerase chain reaction [letter] [In Process Citation]. Diagn Mol Pathol 7(1):63–64

Shen DF, Zhuang Z, LeHoang P, Boni R, Zheng S, Nussenblatt RB et al (1998) Utility of microdissection and polymerase chain reaction for the detection of immunoglobulin gene rearrangement and translocation in primary intraocular lymphoma [In Process Citation]. Ophthalmology 105(9):1664–1669

Wang Y, Shen D, Wang VM, Sen HN, Chan CC (2011) Molecular biomarkers for the diagnosis of primary vitreoretinal lymphoma. Int J Mol Sci 12:5684–5697

Levy-Clarke GA, Buggage RR, Shen D, Vaughn LO, Chan CC, Davis JL (2002) Human T-cell lymphotropic virus type-1 associated T-cell leukemia/lymphoma masquerading as necrotizing retinal vasculitis. Ophthalmology 109(9):1717–1722

Levy-Clarke GA, Byrnes GA, Buggage RR, Shen DF, Filie AC, Caruso RC et al (2001) Primary intraocular lymphoma diagnosed by fine needle aspiration biopsy of a subretinal lesion. Retina 21(3):281–284

Buggage RR, Velez G, Myers-Powell B, Shen D, Whitcup SM, Chan CC (1999) Primary intraocular lymphoma with a low interleukin 10 to interleukin 6 ratio and heterogeneous IgH gene rearrangement. Arch Ophthalmol 117(9):1239–1242

Gonzales JA, Chan CC (2007) Biopsy techniques and yields in diagnosing primary intraocular lymphoma. Int Ophthalmol 27(4):241–250

Cassoux N, Charlotte F, Rao NA, Bodaghi B, Merle-Beral H, Lehoang P (2005) Endoretinal biopsy in establishing the diagnosis of uveitis: Ocul Immunol Inflamm 13(1):79–83

Sen HN, Bodaghi B, Hoang PL, Nussenblatt R (2009) Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm 17:133–141

Wender A, Adar A, Maor E et al (1994) Primary B-cell lymphoma of the eyes and brain in a 3-year-old boy. Arch Ophthalmol 112:450–451

Ferreri AJ, Blay JY, Reni M et al (2002) Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 13:531–538

Hoffman PM, McKelvie P, Hall AJ et al (2003) Intraocular lymphoma: a series of 14 patients with clinicopathological features and treatment outcomes. Eye 17:513–521

Isobe K, Ejima Y, Tokumaru S et al (2006) Treatment of primary intraocular lymphoma with radiation therapy: a multi-institutional survey in Japan. Leuk Lymphoma 47:1800–1805

Berenbom A, Davila RM, Lin HS et al (2007) Treatment. Outcomes for primary intraocular lymphoma: implications for external beam radiotherapy. Eye 21:1198–1201

Jahnke K, Korfel A, Komm J, Bechrakis NE, Stein H, Thiel E et al (2006) Intraocular lymphoma 2000–2005: results of a retrospective multicentre trial. Graefes Arch Clin Exp Ophthalmol 244(6):663–669

Grimm SA, Pulido JS, Jahnke K et al (2007) Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18:1851–1855, Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 13:531–538

Grimm SA, McCannel CA, Omuro AM (2008) Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report. Neurology 71:1355–1360

Char DH, Margolis L, Newman AB (1981) Ocular reticulum cell sarcoma. Am J Ophthalmol 91:480–483

Batchelor TT, Kolak G, Ciordia R et al (2003) High-dose methotrexate for intraocular lymphoma. Clin Can Res 9:711–715

Sandor V, Stark-Vancs V, Pearson D et al (1998) Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16:3000–3006

Glantz MJ, Cole BF, Recht L et al (1998) High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 16:1561–1567

Cher L, Glass J, Harsh GR et al (1996) Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology 46:1757–1759

Guha-Thakurta N, Damek D, Pollack C et al (1999) Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol 43:259–268

Herrlinger U, Küker W, Uhl M et al (2005) NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 57:843–847

Khan RB, Shi W, Thaler HT et al (2002) Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol 58:175–178

Taoka K, Yamamoto G, Kaburaki T, Takahashi T, Araie M, Kurokawa M (2011) Treatment of primary intraocular lymphoma with rituximab, high dose methotrexate, procarbazine, and vincristine chemotherapy, reduced whole-brain radiotherapy, and local ocular therapy. Br J Haematol 157:252–254

Article PubMed CAS Google Scholar

Reni M, Zaja F, Mason W et al (2007) Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 96:864–867

Kurzwelly D, Glas M, Roth P, Weimann E, Lohner H, Waha A, Schabet M, Reifenberger G, Weller M, Herrlinger U (2010) Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status. J Neurooncol 97:389–392

Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (alliance 50202). J Clin Oncol 31:3061–3068

Wang Y, Liu B, Xu D, Zhao H, Zhu Y, Xu J, Tao R (2013) Phase II trial of temozolomide plus concurrent whole-brain radiation followed by TNV regimen as adjuvant therapy for patients with newly diagnosed primary CNS lymphoma. Neurol India 61:260–264

Jaglowski SM, Alinari L, Lapalombella R, Muthusamy N, Byrd JC (2010) The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 116:3705–3714

Coiffier B, Lepage E, Briere J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

Pfreundschuh M, Trümper L, Osterborg A et al (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391

Wolf T, Kiderlen T, Atta J et al (2014) Successful treatment of AIDS-associated, primary CNS lymphoma with rituximab- and methotrexate-based chemotherapy and autologous stem cell transplantation. Infection 42:445–447

Google Scholar

Oki Y, Westin JR, Vega F, Chuang H et al (2013) Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol 163:611–620

Morris PG, Correa DD, Yahalom J et al (2013) Rituximab, methotrexate, procarbazine and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 31:3971–3979

Pels H, Schmidt-Wolf IG, Glasmacher A et al (2003) Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21:4489–4495

Smith JR, Rosenbaum JT, Wilson DJ et al (2002) Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology 109:1709–1716

Frenkel S, Hendler K, Siegal T et al (2008) Intravitreal methotrexate for treating vitreoretinal lymphoma: ten years of experience. Br J Ophthalmol 92:383–388

Fishburne BC, Wilson DJ, Rosenbaum JT et al (1997) Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 115:1152–1156

Kitzmann AS, Pulido JS, Mohney BG et al (2007) Intraocular use of rituximab. Eye 21:1524–1527

Hashida N, Ohguro N, Nishida K (2012) Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma. Transl Vis Sci Technol 1:1

Ohguro N, Hashida N, Tano Y (2008) Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma. Arch Ophthalmol 126:1002–1003

Pe’er J, Hochberg FH, Foster CS (2009) Clinical review: treatment of vitreoretinal lymphoma. Ocul Immunol Inflamm 17:299–306

Yeh S, Wilson DJ (2010) Combination intravitreal rituximab and methotrexate for massive subretinal lymphoma. Eye 24:1625–1627

Wong ET (2005) Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 64:934

Soussain C, Hoang-Xuan K, Taillandier L et al (2008) Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol 26:2512–2518

Soussain C, Choquet S, Fourme E et al (2012) Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases. Haematologica 97:1751–1756

DeAngelis LM (1999) Primary central nervous system lymphoma. Curr Opin Neurol 12(6):687–691

Panageas KS, Elkin EB, DeAngelis LM, Ben-Porat L, Abrey LE (2005) Trends in survival from primary central nervous system lymphoma. Cancer 104(11):2466–2472

DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20(24):4643–4648

Shibamoto Y, Tsuchida E, Seki K, Oya N, Hasegawa M, Toda Y et al (2004) Primary central nervous system lymphoma in Japan 1995–1999: changes from. J Cancer Res Clin Oncol 130(6):351–356

Kimura K, Usui Y, Goto H (2012) Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol 56(4):383–389

Abrey LE, Yahalom J, DeAngelis LM (2000) Treatment for primary CNS lymphoma: the next step. J Clin Oncol 18(17):3144–3150

Corry J, Smith JG, Wirth A, Quong G, Liew KH (1998) Primary central nervous system lymphoma: age and performance status are more important than treatment modality. Int J Radiat Oncol Biol Phys 41(3):615–620

Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D et al (2004) Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 350(18):1828–1837

Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al (2004) Prediction of survival in follicular lymphoma based on molecular features. N Engl J Med 351(21):2159–2169

Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V et al (2005) Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene expression-based survival prediction. Blood 106:3183–3190

Coupland SE, Chan CC, Smith J (2009) Pathophysiology of retinal lymphoma. Ocular immunology and inflammation 17:227–237

Casady M, Faia L, Nazemzadeh M et al (2014) Fundus autofluorescence patterns in primary intraocular lymphoma. Retina 34:366–372

Sagoo MS, Mehta H, Swampillai AJ et al (2014) Primary intraocular lymphoma. Survey of ophthalmology 59:503–516

Download references

Author information

Authors and affiliations.

Section of Immunopathology, Laboratory of Immunology, National Eye Institute, Bethesda, MD, USA

Chi-Chao Chan MD

Department of Internal Medicine, University of Tuebingen, Tuebingen, Germany

Sebastian P. Haen & Robert Möhle

Center of Ophthalmology, University of Tuebingen, Tuebingen, Germany

Manfred Zierhut MD

You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manfred Zierhut MD .

Editor information

Editors and affiliations.

Centre of Ophthalmology, University of Tuebingen, Tuebingen, Germany

Manfred Zierhut

Biomedical Research Centre, Institute of Ophthalmology, Moorfields Eyes Hospital, Department of Medical Retina, UCL, London, United Kingdom

Carlos Pavesio

School of Medicine, Department of Ophthalmology, Hokkaido University Graduate, Sapporo, Hokkaido, Japan

Shigeaki Ohno

University of Belo Horizonte, Belo Horizonte, Brazil

Fernando Orefice

USC Eye Institute, University of Southern California, Los Angeles, California, USA

Narsing A. Rao

1 Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Case Report 12

Intraocular lymphoma (PPT 3141 kb)

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Chan, CC., Haen, S.P., Möhle, R., Zierhut, M. (2016). Primary Intraocular Lymphoma. In: Zierhut, M., Pavesio, C., Ohno, S., Orefice, F., Rao, N. (eds) Intraocular Inflammation. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-75387-2_147

Download citation

DOI : https://doi.org/10.1007/978-3-540-75387-2_147

Publisher Name : Springer, Berlin, Heidelberg

Print ISBN : 978-3-540-75385-8

Online ISBN : 978-3-540-75387-2

eBook Packages : Medicine Medicine (R0)

Share this chapter

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Publish with us

Policies and ethics

Find a journal
Track your research

Case report
Open access
Published: 03 October 2016

Atypical presentation of primary intraocular lymphoma

Koji Komatsu 1 ,
Tsutomu Sakai 1 ,
Toshikatsu Kaburaki 2 ,
Hideki Tsuji 3 &
Hiroshi Tsuneoka 1

BMC Ophthalmology volume 16 , Article number: 171 ( 2016 ) Cite this article

1478 Accesses

4 Citations

1 Altmetric

Metrics details

In 2014, Pang et al. reported three cases with vitelliform submaculopathy as a preceding lesion of primary intraocular lymphoma (PIOL). Here, we report a case with an atypical presentation of PIOL who initially presented with vitelliform submaculopathy, vitreous haze and preripheral retinal focus.

Case presentation

A 73-year-old female initially visited another hospital with a chief complaint of acute reduced vision in the right eye. Funduscopic examination of the right eye showed a yellowish retinal lesion at the fovea with vitreous haze and retinal foci scattered in the peripheral region. Spectral-domain optic coherence tomography (SD-OCT) revealed a hyperreflective subretinal debris above the retinal pigment epithelium (RPE) at the fovea, suggesting vitelliform submaculopathy. Vitrectomy was performed to improve visualization of the retinal lesions and for examination of PIOL. Vitreous cytology was class III and cytokine analysis of vitreous fluid showed increased IL-10 and an IL-10/IL-6 ratio >1, suggesting PIOL. Thereafter, there was a sub-RPE infiltration of presumed lymphoma in the nasal retina, and PCR analysis of anterior chamber fluid indicated IgH gene rearrangement, leading to diagnosis of PIOL. Three months later, there was complete disappearance of the vitelliform submacular lesion, with resultant disruption and thinning of the outer retinal layers on SD-OCT images.

Conclusions

Clinicians should be aware of atypical manifestations of PIOL such as vitelliform submaculopathy and peripheral retinal foci with vitreous haze. The patient’s unusual funduscopic changes are findings that have not reported in patients with PIOL.

Intraocular lymphomas are a rare form of ocular malignancy and involve two types. Primary intraocular lymphoma (PIOL) affects the vitreous, retina, choroid or optic nerve and secondary intraocular lymphoma is seen in patients who have systemic lymphoma [ 1 ]. This disease has a poor prognosis with a 5-year survival rate of 61 %, and the incidence has increased recently [ 2 ]. The disease is typical of masquerade syndromes and is often difficult to diagnose if no characteristic vitreous haze or subretinal focus is present. In 2014, Pang et al. described three cases in which vitelliform submaculopathy preceded typical lesions of PIOL, as the first report of this event [ 3 ]. Foci in those cases spontaneously disappeared in a brief period, with a subsequently diagnosis of PIOL. Here, we describe an atypical presentation of PIOL in a patient who initially presented with vitelliform submaculopathy, vitreous haze and preripheral retinal focus, in which PIOL was diagnosed in the subsequent course.

The patient was a 73-year-old Japanese woman who had been suffering from visual loss and a history of floaters in the right eye from May 2012. The right eye had vitreous haze and retinal white foci in the peripheral fundus, the causes of which were unclear in a detailed examination. For further examination and treatment, she was referred to Jikei University Hospital and visited in June 2012. She was immunocompetent and had no underlying systemic diseases.

On presentation, the best-corrected visual acuity (BCVA) was 0.02 OD and 1.2 OS. There was no relative afferent pupillary defect. The patient had no cells in the anterior chamber and diffuse vitreous cells with trace haze in the right eye. Funduscopic examination of the right eye showed a yellow submacular lesion at the fovea, in addition to vitreous haze and retinal foci scattered in the peripheral region (Fig. 1a ). The left eye appeared normal. Spectral-domain optic coherence tomography (SD-OCT) revealed hyperreflective subretinal debris resembling vitelliform deposition above the retinal pigment epithelium (RPE) band (Fig. 1b ). Fluorescein angiography (FA) imaging showed multiple hyperfluorescent lesions of various sizes in the peripheral region (Fig. 1c ). Serologic test results, including those for antitoxoplasma IgG and IgM antibodies, angiotensin-converting enzyme, and viral antibodies such as herpes simplex virus, varicella zoster virus and cytomegalovirus, were within normal limits. Chest X-ray and magnetic resonance imaging were unremarkable.

Fundus photograph, fluorescein angiography and spectral-domain optical coherence tomography (SD-OCT) at initial presentation. a . Fundus photograph showing submacular yellow material at the fovea and multiple peripheral retinal foci. b . Fluorescein angiography showing multiple hyperfluorescent peripheral lesions. c . SD-OCT revealed hyperreflective material deposition above the retinal pigment epithelium (RPE) band consistent with submacular yellow material

Vitreous haze slowly worsened within a few months. A 25-gauge pars plana vitrectomy was performed to improve visualization of the retinal lesions and for examination of causative microorganisms or PIOL. Vitreous cytology was class III and the cytokine analysis of vitreous fluid revealed increased IL-10 and an IL-10/IL-6 ratio >1, suggesting PIOL. Three months later, there were appearances of new multiple yellow-white sub-RPE infltrates in the peripheral fundus (Fig. 2a, c ). At this time, SD-OCT still showed a hyperreflective material above the RPE band (Fig. 2b ). PCR analysis of the anterior chamber fluid revealed IgH gene rearrangement, thus allowing a definitive diagnosis of PIOL. In a few months later, SD-OCT revealed hyperreflective bands and nodules above the RPE band with regression of the vitelliform debris (Fig. 3 ). Finally, the patient decided to treat with intravitreal methotrexate injections (weekly 400 μg/100 mL for 6 weeks). The patient has survived with a total-follow up of 31 months, with no invlolvement of the central nervous system. The right eye has remained recurrence-free 24 months after the 20th intravitreal methotrexate injections. BCVA improved to 0.4 in the right eye.

Fundus photograph and spectral-domain optical coherence tomography (SD-OCT) at 3 months after initial visit. a . Fundus photograph showing sub-retinal pigment epithelium (RPE) white mass in the temporal region. b . There was decrease in the vitelliform debris at the fovea seen with SD-OCT. c . SD-OCT revealed steep elevation of the RPE band consistent with sub-RPE mass

Fundus photograph and spectral-domain optical coherence tomography (SD-OCT) at 6 months after initial visit. a . Fundus photograph showing multiple sub-retinal pigment epithelium (RPE) white mass in the temporal and nasal region. b . There was decrease in the vitelliform debris at the fovea seen with SD-OCT. C. SD-OCT revealed complete resolution of the vitelliform debris and hyperreflective nodules at the RPE level

This case highlights some atypical features that can be associated with PIOL. On initial presentation, vitreous haze, vitelliform submaculopathy and peripheral retinal foci were present simultaneously, with subsequent appearance of sub-RPE infiltrates, a typical lesion of PIOL. This was followed by multiple lesion occurrence and growth, together with spontaneous disappearance of vitelliform submaculopathy.

In 2014, Pang et al. reported three cases in which vitelliform submaculopathy preceded typical lesions of PIOL [ 3 ]. Our case has several different features in clinical course, unlike their cases. First, our case presented with vitreous haze, vitelliform submaculopathy and peripheral retinal foci as an initial presentation, in contrast to Pang et al. cases. Secondly, in our case, there was development of sub-RPE infiltration in the peripheral retina without regression of vitelliform submaculopathy. Although Pang et al. pointed out the importance of vitelliform submaculopathy as a preceding lesion in PIOL, we thus think this condition may be involved in one of initial manifestations of PIOL. Finally, there was an occurrence of hyperreflective nodules at the RPE level and disruption of the ellipsoid zone after complete disappearance of vitelliform submaculopathy. In 13 cases of PIOL described by Keino et al., nearly one-half of the cases involved hyperreflective nodules at the RPE level and disruption of the ellipsoid zone during follow-up [ 4 ]. Although Keino et al. did not investigate an association SD-OCT patterns with clinical course, we suggest that the occurrence of vitelliform submaculopathy can be an early form of lymphoma-associated retinopathy and this condition may be seen with various manifestations in the initial phase of PIOL.

PIOL can present with atypical fundus manifestations such as vitelliform submaculopathy and peripheral retinal foci with vitreous haze. SD-OCT may be useful for early detection and monitoring of small macular abnormalities in this disease.

Abbreviations

Best-corrected visual acuity

Primary intraocular lymphoma

Retinal pigment epithelium

Spectral-domain optic coherence tomography.

Chan CC, Buggage RR, Nussenblatt RB. Intraocular lymphoma. Curr Opin Ophthalmol. 2002;13:411–18.

Article PubMed Google Scholar

Kimura K, Usui Y, Goto H. Japanese Intraocular Lymphoma Study Group. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol. 2012;56:383–9.

Pang CE, Shields CL, Jumper JM, Yannuzzi LA. Paraneoplastic cloudy vitelliform submaculopathy in primary vitreoretinal lymphoma. Am J Ophthalmol. 2014;158:1253–61.

Keino H, Okada AA, Watanabe T, Echizen N, Inoue M, Takayama N, et al. Spectral-domain Optical Coherence Tomography Patterns in Intraocular Lymphoma. Ocul Immunol Inflamm. 2015;24:1–6.

Article Google Scholar

Download references

Acknowledgements

The authors have no financial support in this study.

The case report has no funding involved.

Availability of data and materials

All data supporting our findings will be shared upon request, although the majority is contained within the manuscript.

Authors’ contributions

KK, TS and HT (Hiroshi Tsuneoka) carried out the initial chart reviewing and drafted the manuscript. KK, TS, TK, and HT (Hideki Tsuji) added details to the initial case report, and participated in its overall design. All authors read and approved the final manuscript.

Competing interests

The authors report no competing interests. The authors alone are responsible for the content and writing of the paper.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Ethics approval and consent to participate

Not applicable.

Author information

Authors and affiliations.

Department of Ophthalmology, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461, Japan

Koji Komatsu, Tsutomu Sakai & Hiroshi Tsuneoka

Department of Ophthalmology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

Toshikatsu Kaburaki

Department of Ophthalmology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

Hideki Tsuji

You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsutomu Sakai .

Additional information

Submitting author: Koji Komatsu, Department of Ophthalmology, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Cite this article.

Komatsu, K., Sakai, T., Kaburaki, T. et al. Atypical presentation of primary intraocular lymphoma. BMC Ophthalmol 16 , 171 (2016). https://doi.org/10.1186/s12886-016-0350-x

Download citation

Received : 13 March 2016

Accepted : 13 June 2016

Published : 03 October 2016

DOI : https://doi.org/10.1186/s12886-016-0350-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Vitelliform submaculopathy
Spectral-domain optic coherence tomography

BMC Ophthalmology

ISSN: 1471-2415

General enquiries: [email protected]

IMAGES

Intraocular lymphoma
Primary Intraocular Lymphoma
Primary intraocular lymphoma
Primary intraocular lymphoma
Intraocular Lymphoma
Primary Intraocular Lymphoma Seen With Transient White Fundus Lesions

VIDEO

Update on the basics of intraocular lymphoma by Sarah Coupland, MBBS, PhD
Primary gastric lymphoma #radiology #core #abr
7th RCS: Primary Thyroid Lymphoma
Primary Pulmonary Hodgkin's Lymphoma
Intraocular Tumors: Session 6: Malignant Intraocular Tumors
Primary Effusion Lymphoma: A Rare Case Presentation

COMMENTS

Primary Intraocular Lymphoma
Primary intraocular lymphoma (PIOL) is a rare ocular malignancy and is considered as a subset of primary central nervous system lymphoma (PCNSL) with ocular involvement.[1] It is an extranodal non-Hodgkin, diffuse large B cell lymphoma. It was earlier known as "malignant lymphoma of the uveal tract" and "reticulum cell sarcoma," which was misleading, and hence, these names went out of ...
Intraocular Lymphoma
Intraocular Lymphoma. by Christina Y. Weng, MD, MBA on March 4, 2024. Primary intraocular lymphoma often poses a diagnostic dilemma with presentation like vitritis, intermediate uveitis or subretinal plaque-like lesions [1]. Diagnosis is often challenging in such cases, and this is why it is often one of the diseases referred to as a masquerade ...
Diagnosis & Treatment of Intraocular Lymphoma
For this reason, secondary lymphoma can have a similar clinical appearance to primary choroidal lymphoma. 36 Rarely, a spread to the retina (See Figure 4) without choroidal infiltration can occur. 36 Other exceptional presentations of secondary intraocular lymphoma include pseudohypopyon and iris infiltration. 37,38 While exceedingly rare ...
Primary Vitreoretinal Lymphoma
Primary vitreoretinal lymphoma (PVRL) has many names, including primary intraocular lymphoma or intraocular reticulum cell sarcoma, and it is a manifestation of primary central nervous system lymphoma (PCNSL). ... Clinical Presentation. The disease's insidious onset coupled with vague complaints from patients with PVRL are among the factors ...
Learning points in intraocular lymphoma
If the presentation is bilateral or there is CNS involvement, ... Fundus autofluorescence patterns in eyes with primary intraocular lymphoma. Retina. 2010;30:23-32. Article Google Scholar
Diagnosis and management of primary intraocular lymphoma: an update
Primary intraocular lymphoma (PIOL) is a malignant non-Hodgkin's lymphoma (NHL) which either occurs independently to, or in association with primary central nervous system lymphoma (PCNSL). It involves the retina, the vitreous chamber and/or the optic nerve and has to be distinguished from secondary intraocular lymphoma (IOL), an ocular ...
Epidemiology and survival outcomes of patients with primary intraocular
Primary intraocular lymphoma (PIOL) is a rare malignancy with a poor prognosis, but its optimal therapy remains unclear. Herein, we aimed to analyze the epidemiology and survival outcomes of PIOL patients based on a population-based cancer registry in the United States. Patients diagnosed with PIOL between 1992 and 2018 were identified from the Surveillance Epidemiology and End Results program.
Primary Intraocular Lymphoma
Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haemotol. 2004; 126: 202-208. Crossref; ... Primary intraocular lymphoma is a subset of non-Hodgkin's B-cell nervous system lymphoma. In Finland, with a population of 5.2 million, 118 new cases of PNSL were registered by the Finnish Cancer Registry ...
Intraocular Lymphoma: Clinical Presentation and Imaging Studies
Abstract. Primary intraocular lymphoma (PIOL) is a malignant neoplasm derived from monoclonal proliferations of B- or T-lymphocytes and is classified according to its location into either primary vitreoretinal lymphoma or primary uveal lymphoma. PCNSL-O is the preferred term for vitreoretinal lymphoma to emphasize that it is an ocular variant ...
Intraocular lymphoma: a clinical perspective
Primary vitreoretinal lymphoma (PVRL) is a rare malignancy that is speculated to arise extraocularly, and preferentially invade and flourish in the ocular and CNS microenvironments. The eye is ...
Primary intraocular lymphoma: a review of the clinical ...
Introduction Primary intraocular lymphoma (PIOL) is a rare non-Hodgkin lymphoma which arises in the retina or the vitreous. It can occur either together with or independently of primary cerebral nervous system lymphoma (PCNSL); the incidence of the latter has significantly increased over the past three decades. PIOL remains one of the most difficult diagnoses to establish, particularly due to ...
Variations in the Presentation of Primary Intraocular Lymphoma
Primary intraocular lymphoma is a distinct subset of primary non-Hodgkin's lymphoma of the central nervous system (CNS). Diagnosis can be difficult and is often delayed, as the clinical presentation can mimic a number of other ocular conditions. This report describes four different presentations of intraocular lymphoma and focuses on its modes of clinical presentation.
Primary Intraocular Lymphoma
Primary intraocular lymphoma (PIOL) is a neoplasm, most frequently of B-cell and rarely T-cell origin arising from or initially presenting in the eye [1, 2].PIOL of the B-cell type is a non-Hodgkin's lymphoma of the diffuse large B-cell type that belongs within the category of primary central nervous system lymphoma (PCNSL) [].The lymphoma always is located in the subretinal space, retina ...
Atypical presentation of primary intraocular lymphoma
Intraocular lymphomas are a rare form of ocular malignancy and involve two types. Primary intraocular lymphoma (PIOL) affects the vitreous, retina, choroid or optic nerve and secondary intraocular lymphoma is seen in patients who have systemic lymphoma [ 1 ]. This disease has a poor prognosis with a 5-year survival rate of 61 %, and the ...
Variations in the Presentation of Primary Intraocular Lymphoma: Case
Primary intraocular lymphoma is a distinct subset of primary non-Hodgkin's lymphoma of the central nervous system (CNS). Diagnosis can be difficult and is often delayed, as the clinical presentation can mimic a number of other ocular conditions.

StatPearls [Internet].

Affiliations

In this Page

Related information

Similar articles in PubMed

Recent Activity

Intraocular Lymphoma

Clinical diagnosis

Fluorescein Angiography

Optical coherence tomography

Fundus autofluorescence

Diagnostic vitrectomy

Systemic Evaluation

Medical therapy

Local Chemotherapy

Systemic Chemotherapy

Additional Resources

Diagnosis & Treatment of Intraocular Lymphoma

Table of Contents

Primary Vitreoretinal Lymphoma

Epidemiology

Association With CNS Lymphoma

Clinical Presentation

Treatment and Prognosis

FOLLOW THE ACADEMY

Intraocular lymphoma: a clinical perspective

Methodology

Clinical correlations with the pathogenesis of PVRL

Clinical features of PVRL

Diagnosis of intraocular lymphoma

Future directions

Acknowledgements

Author information

Corresponding author

Ethics declarations

Additional information

Rights and permissions

About this article

Share this article

This article is cited by

First observation of intraocular extranodal natural killer/T-cell lymphoma secondary to a retroperitoneal tumour: a case report and comparative review

Epidemiology and survival outcomes of patients with primary intraocular lymphoma: a population-based analysis

Clinical sign and symptom of primary vitreoretinal lymphoma short-time after retinal reattachment surgery: a case report

Quick links

Primary Intraocular Lymphoma

Cite this chapter

Access this chapter

Author information

Corresponding author

Editor information

1 Electronic Supplementary Material

Case Report 12

Rights and permissions

Copyright information

About this chapter

Download citation

Share this chapter

Atypical presentation of primary intraocular lymphoma

Case presentation

Conclusions

Abbreviations

Acknowledgements

Availability of data and materials

Authors’ contributions

Competing interests

Consent for publication

Ethics approval and consent to participate

Author information

Corresponding author

Additional information

Rights and permissions

About this article

Share this article

BMC Ophthalmology

IMAGES

VIDEO

COMMENTS