Primary Intraocular Lymphoma

Sriram Simakurthy; Soumya Jena; Koushik Tripathy

Primary Intraocular Lymphoma

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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.

Objectives:

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]

Etiology

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]

Evaluation

Imaging
Biopsy & analysis
Blood tests

Imaging	Optical coherence tomography (OCT) Fundus fluorescein angiography (FFA) Indocyanine green angiography (ICGA) Fundus autofluorescence (FAF) Ultrasonography (USG) Neuroimaging
Biopsy and analysis	Histopathology Immunohistochemistry Cytokine analysis Polymerase chain reaction
Blood tests	To rule out common uveitic conditions and other masquerades

I. Imaging

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]

Analysis

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 chemotherapy, Radiation, Vitrectomy
Systemic Therapy	Chemotherapy, Chemoradiation

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]

Vitrectomy

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.

Rituximab

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]

Ibrutinib

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

Neoplasms

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]

Prognosis

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.

(Click Image to Enlarge)

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

(Click Image to Enlarge)

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

(Click Image to Enlarge)

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

(Click Image to Enlarge)

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

(Click Image to Enlarge)

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

Details

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