Overview

Whereas Hodgkin lymphoma very rarely causes ocular disease, non-Hodgkin lymphoma

(NHL) is the most common type of ocular lymphoma. Depending on the site of

involvement, ocular lymphoma can be either intraocular or orbital and adnexal.

The most common presentation of intraocular lymphoma is decreased vision with

nonresolving uveitis. Diagnosis is often based on obtaining an intraocular biopsy

specimen. Optimal management is not yet realized. Chemoradiation is the most effective

treatment, but significant ocular and cerebral morbidity is associated with its use.

Lymphoma has been described as the most common malignant orbital tumor, representing

55% of cases in adults[1]and 10% of cases in older patients.[2, 3]Lymphoproliferative

disease of the orbit usually presents later in life and causes symptoms due to gradually

increasing mass effect. Proptosis and visible conjunctival mass are the common modes of

presentation. It tends to be localized to the orbit at the time of diagnosis and responds

well to local or systemic therapy.[4]

Orbital and adnexal lymphoma is associated with systemic lymphoma in 30-35% of

cases. Hence, all patients with ocular lymphoma should have a complete workup to rule

out systemic lymphoma.

Over the years, different systems have been used to classify lymphomas, including the

Rappaport Classification (used until the 1970s), the Working Formulation, the National

Cancer Institute Working Formulation, and the Revised European-American Lymphoma

Classification (REAL). In 2001, a modern comprehensive classification system was

published under the auspices of the World Health Organization (WHO); this represents

the first worldwide consensus document on the classification of lymphoma.[5]

The prognosis for ocular lymphoma depends on the tumor’s histologic type and stage, as

well as on the treatment employed. In general, with modern treatment of patients with

NHL, the overall survival rate at 5 years is approximately 60%.

Pathophysiology

Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest

a role for infectious agents in the pathogenesis of intraocular lymphoma.

Extramarginal zone lymphomas, which account for most primary orbital and adnexal

lymphomas, are characterized by an indolent natural history with frequent, continuous

extranodal relapses.[6]Follicular lymphoma, diffuse large B cell lymphoma, mantle cell

lymphoma, B-cell chronic lymphocytic leukemia, peripheral T-cell lymphoma, and

natural killer cell lymphoma have also been reported to affect the orbit.

Several hypotheses explain the increasing incidence of non-Hodgkin lymphoma (NHL).

Better imaging techniques, improved biopsy techniques, and newer classification systems

are likely to have contributed to the apparent increase in the incidence of lymphoma. The

aging population, the increasing number of immunosuppressive drugs, and the AIDS

epidemic have also contributed to the increased incidence of NHL.

Chlamydia psittaci is associated with ocular adnexal mucosa-associated lymphoid tissue

(MALT) lymphoma, and this association varies across different geographical areas. [7, 8]In

South Florida, orbital and adnexal lymphomas are not associated with C psittaci

infections.[6]

Epidemiology

The National Cancer Institute Surveillance, Epidemiology, and End Results program

estimated that in 2008, 2,390 US men and women (1,340 men and 1,050 women) would

be diagnosed with eye cancer and 240 people would die of this disease.[9]

The lifetime risk of being diagnosed with non-odgkinHHodgkiHNHL is 2.08%. From

1975-2001, a rapid and steady increase occurred in the incidence of ocular NHL, with

annual increases of 6.2% and 6.5% among white males and white females, respectively.[8]

The incidence of lymphoproliferative ocular diseases, especially malignant lymphoma,

has increased over the years. Lymphoma is the most common primary malignant orbital

tumor in Asian countries like Japan and Korea[10, 11, 12]as well as in Europe.[13]

Intraocular lymphoma is rare, with fewer than 200 cases being reported. This type of

lymphoma is estimated to represent 1% of NHLs, 1% of intracranial tumors, and less than

1% of intraocular tumors.[14]However, over the past 20 years, a steady rise has occurred in

the number of reported cases[15]in both immunocompetent patients and

immunocompromised patients.[16]

Incidence of ocular lymphoma increases with advancing age.[8]Intraocular lymphoma

typically affects elderly patients, with reported series having mean ages in the seventh

decade of life. The median age at presentation for orbital and adnexal lymphoma is older

than 60 years. In a study conducted in the United States, malignant lymphoma was the

most common orbital tumor in the elderly age group, accounting for 24% of cases.[17]

No sex predilection was noted for ocular lymphomas in some studies. [8]However, in cases

of intraocular lymphoma, women are known to be affected up to twice as often as men.

Orbital lymphoma was found to have a female preponderance.[4]During 1992–2001,

ocular NHL rates per 100,000 person-years for both sexes were highest among

Asians/Pacific Islanders, lower in whites, and lower still in blacks.[8]

Clinical Presentation

The symptoms reported differ according to whether the lymphoma is intraocular or

orbital and adnexal.

Intraocular lymphoma

There are 2 distinct forms of intraocular lymphoma. When the ocular disease appears to

be a subset of primary central nervous system (CNS) lymphoma (PCNSL), the term

“primary CNS lymphoma with ocular involvement” (PCNSLO) is used. In these cases,

intraocular lymphoma can precede CNS involvement by months or years. The second

form of intraocular lymphoma arises outside the CNS and metastasizes to the eye.

Intraocular lymphoma has been divided anatomically into vitreoretinal and uveal forms.

The vitreoretinal form is associated with PCNSL and is typically a large B-cell tumor

(intermediate-grade lymphoma). In contrast, the uveal form is associated with systemic

NHL and also with involvement of orbital structures. It is typically small B-cell

proliferation (low-grade lymphoma) and usually occurs with advanced systemic disease.

Rare cases of T-cell lymphoma with ocular involvement have been reported.

On initial presentation, PCNSLO may be either unilateral or bilateral, but ultimately, 80-

90% of patients have bilateral involvement. Intracranial disease occurs in 56-85% of

patients with ocular disease, and estimates suggest that 15-25% of patients who present

with CNS disease have ocular disease—hence the distinction between PCNSL and

PCNSLO.[18, 19, 20, 21, 22]

The typical clinical profile is an elderly patient with uveitis that is refractory to treatment.

The most common subjective symptoms are painless decreased vision, photophobia, red

eye, and floaters. In some patients with known PCNSL, ocular disease may be discovered

on routine screening. Because of its insidious onset and ability to simulate other

conditions, delay in diagnosis is common.

Vision loss is frequent in PCNSLO and may range from mild to severe. With extensive

disease, circulating tumor cells can appear in the anterior chamber in as many as 75% of

patients. The cells simulate iridocyclitis and can even form a pseudohypopyon.

Secondary anterior segment changes include neovascularization of the iris and

iridocorneal angle with possible glaucoma. In rare circumstances, PCNSLO can form a

mass in the iris or angle.

In the posterior segment, vitreous cells are a typical finding and are present in most cases.

The characteristic fundus lesion is a low-lying, yellow-to-white mass deep to the sensory

retina. Lesions may be single or multiple, confluent or discrete. They may even appear as

multiple punctate lesions.

Lesions may be infiltrative and involve all layers of the retina. Retinal hemorrhage is

rarely seen. The deep location of the infiltrates can give rise to exudative retinal

detachment. If chorioretinal lesions regress, scarring and atrophy of the retinal pigment

epithelium may be the only remaining fundus findings. Optic neuropathy may also be a

feature.[18, 19, 20, 21, 22]

PCNSLO appears to occur with increased frequency in persons who are severely

immunosuppressed.

Metastatic systemic lymphoma, like other metastatic ocular tumors, is usually confined to

the uvea—in particular, the choroid. Compared with PCNSLO, metastatic systemic

lymphomas are much less prevalent, have a better prognosis, and are less likely to create

a diagnostic dilemma.[23]

Orbital and adnexal lymphoma

Orbital and ocular adnexal lymphoma has an insidious onset and can progress slowly for

over a year before producing symptoms. Symptoms are usually secondary to pressure

effects on surrounding structures. Clinical features include painless proptosis with or

without motility disturbances, double vision, ptosis, and, rarely, decreased vision. The

lesions can be unilateral or bilateral. Lymphomatous lesions can involve the preseptal

portion of the eyelid.

Orbital lymphomas present with painless proptosis, the lesions being more common in

the anterior superior orbit. The mass is usually rubbery to firm on palpation with no

palpable bony destruction. The lacrimal gland, lacrimal sac, and extraocular muscles can

also be similarly involved.

Orbital lymphoma can also occur in patients with AIDS.[24, 25]

Conjunctival lymphoma has a characteristic salmon-pink appearance (see the image

below). It may be an extension of orbital or intraocular lymphoma.

Salmon-pink appearance of conjunctival lymphoma.

Simultaneous occurrence of intraocular and orbital lymphoma does occur but is rare.[26]

The presence of cervical or preauricular lymphadenopathy, parotid gland swelling, or an

abdominal mass can signify systemic disease. Hence, a thorough physical evaluation

should be carried out in all patients with ocular lymphoma.

Differential Diagnosis

The differential diagnosis for primary central nervous system lymphoma with ocular

involvement (PCNSLO) includes reactive lymphoid hyperplasia (RLH), spread of

systemic lymphoma, primary uveitis, infection, metastatic tumor, and amelanotic

melanoma. All of these (except uveal melanoma) may not uncommonly have central

nervous system (CNS) involvement.

Primarily vitreoretinal involvement supports the diagnosis of PCNSLO, whereas

primarily choroidal involvement and evidence of other non-Hodgkin lymphoma (NHL)

supports metastatic spread to the choroid. Large cell intraocular lymphoma with retinal

involvement can mimic cytomegalovirus retinitis.

Conjunctival lymphoma should be included in the differential diagnoses of chronic

conjunctivitis. Persisting signs and symptoms of conjunctivitis not responding to standard

treatment should prompt biopsy.[27]

The differential diagnosis for orbital lymphoma include idiopathic inflammatory

pseudotumor, orbital lymphoid hyperplasia, orbital sarcoidosis, Wegener granulomatosis,

and chronic dacryoadenitis.

Laboratory Studies

Laboratory studies are required to address the differential diagnosis of primary central

nervous system lymphoma with ocular involvement (PCNSLO) and orbital lymphoma.

They include the following:

Complete blood count (CBC) with differential

Serum immunoprotein electrophoresis

Rapid plasma reagin (RPR) screening

Erythrocyte sedimentation rate (ESR)

Fluorescent treponemal antibody absorption (FTA-Abs) test

Toxoplasmatiters

Antinuclear antibodies (ANA) test

Rheumatoid factor

Angiotensin-converting enzyme (ACE)

Cytomegalovirus (CMV) titers

A tuberculosis skin test is advisable. The serum lactate dehydrogenase (LDH) level is a

prognostic indicator, with higher levels being indicative of a poorer prognosis. Enzyme-

linked immunosorbent assay (ELISA) for HIV is also recommended.

Imaging Studies

Intraocular lymphoma

B-scan ultrasonography can show the presence of an intraocular mass. In addition, retinal

detachment may be seen. Computed tomography (CT) and magnetic resonance imaging

(MRI) have a low sensitivity for intraocular lymphoma and do not facilitate

differentiating the diagnosis against uveitis or ocular melanoma. [28]Evaluation of patients

with intraocular lymphoma includes high-resolution neuroradiologic imaging of the

central nervous system (CNS) with contrast to look for lesions elsewhere.

Orbital and adnexal lymphoma

CT scan and MRI have made it possible to make a strongly presumptive diagnosis of

orbital lymphoid tumors. They are more reliable than B-scan ultrasonography in the

diagnosis of orbital lymphoma. Positron emission tomography (PET) is useful in selected

settings as well.

CT scan of the orbits is a sensitive investigation that facilitates the diagnosis of orbital

and adnexal lymphoma. On CT scan of the orbits, orbital lymphomas are seen as well-

defined, lobulated or nodular, homogeneous masses of relatively high density and sharp

margins. The lesions mold themselves to preexisting structures without eroding the bone

(see the image below).[29]

Homogeneous isodense orbital mass molding around the

lateral ocular surface.

The following 4 patterns are commonly seen:

Anterior preseptal

Retro-ocular

Lacrimal gland involvement

Extension of a lymphomatous lesion

The lesion is usually extraconal but can extend intraconally as well. Lacrimal gland

disease may involve both orbital lobes and palpebral lobes. The lacrimal sac [30]and

extraocular muscles[31]may also be involved. A streaky appearance may be seen, which

represents irregular infiltration of the microfascial structure of retrobulbar fat.[32]Calcification is rarely seen. Heterogeneous lesions with bony destruction are indicative

of high-grade lymphomas.[33]Bilateral lesions are possible and can signify systemic

disease.

MRI of the orbits possesses good soft tissue definition; however, it lacks the ability to

delineate bone destruction, which can be seen in high-grade lymphomas. MRI may miss

conjunctival disease.[34]

Orbital lesions are usually hypointense[29]or isointense on T1-weighted MRI and

hyperintense on T2-weighted images. Gadolinium enhancement is seen on T1-weighted

images.[33]This is indicative of high cellularity.

Fluorine-18 deoxyglucose PET (FDG-PET) can sometimes find systemic extranodal

lymphomatous sites that are not detected with conventional imaging studies. This ability

yields valuable information in patients with ocular lymphoma, which may result in

important changes in staging and also in patient management.[35, 36]PET has been found to

have a higher sensitivity than CT scan (86% vs 72%) in detecting distant disease.[33]

Other Tests

Lumbar puncture is indicated to obtain cerebrospinal fluid (CSF) for cytology if the

patient is believed to have CNS lymphoma. Bone marrow aspiration is used for staging

systemic lymphomas. CT scans of the chest and abdomen are obtained to rule out

retroperitoneal lymphoma. Bone scans may also be done.

Biopsy

Vitreous biopsy

Vitreous biopsy remains the mainstay of diagnosis for primary central nervous system

lymphoma with ocular involvement (PCNSLO). Vitreous aspiration biopsy is a safe

technique whose advantage is that it best preserves the cytomorphology. Material is

aspirated directly through a 25-gauge needle into a syringe.

A mechanical vitrector provides better management of the tissue during the procedure

and also allows more specimens to be obtained. However, specimens are often diluted

and appear to undergo some artifactitious change, since malignant lymphocytes are

fragile to the effects of mechanical disruption. Material may also be lost in the tubing.

Retinal biopsy

If vitreous samples do not provide diagnostic tissue in the presence of retinal lesions,

retinal and chorioretinal biopsies or subretinal aspiration may be done. Either an

intraocular approach or a transscleral approach can be used.

Orbital biopsy

Biopsy of the lesion is essential to confirm the diagnosis and also to help grade the

lymphoma. The diffuse infiltrating nature of lymphomas may make their complete

excision difficult. Also, their excellent response to irradiation obviates the need for

complete excision.

The route of biopsy is chosen depending on the site of the lesion. Direct approach is

possible for conjunctival and lid lesions, whereas orbitotomy is needed for lesions

involving the lacrimal gland or posterior orbit. In the case of bilateral disease, only 1 orbit

need undergo biopsy.

Histologic Findings

A key factor in obtaining an accurate diagnosis of intraocular lymphoma is a

cytopathologist with experience in intraocular specimens.

Mucosa-associated lymphoid tissue (MALT) lymphoma, diffuse large cell lymphoma,

and small lymphocytic lymphoma are some common types of intraocular lymphoma.

Because of the fragility of neoplastic lymphocytes, a specimen may contain numerous

abnormal-appearing but uninterruptable cells.

Tumor cells can involve the vitreous, retina, optic nerve, or choroid. They are found less

often in the anterior segment. Choroidal involvement by primary central nervous system

lymphoma with ocular involvement (PCNSLO) is typically diffuse, whereas retinal

involvement may be more perivascular. When present, retinal necrosis can be extensive.

Molecular analysis detecting immunoglobulin gene rearrangements and ocular cytokine

levels showing elevated interleukin (IL)–10 (IL-10), with an IL-10–to–IL-6 ratio greater

than 1.0, are helpful adjuncts to cytology for establishing the diagnosis of PCNSLO.[37]CDR3 polymorphism analysis is recommended to confirm clonality.

Extranodal marginal zone B-cell lymphoma represents the most common orbital

lymphoma subtype.[38, 39]Most patients with ocular adnexal lymphoma have stage IE

disease. Immunohistochemical staining with CD markers helps classify lymphomas.

Gross specimens appear salmon-colored with a fish-flesh consistency. Hypercellular

proliferations are seen with sparse stroma. Immunologic identification of cell surface

markers on lymphocytes can be used to classify tumors as containing T or B cells and as

being monoclonal or polyclonal in origin.

The vast majority of orbital lymphomas are of B-cell origin with monoclonal

proliferation from a single neoplastic cell. Well-differentiated monoclonal lesions have

associated systemic disease in 20% of cases, while the association increases to 60% with

less well-differentiated lesions.

The MIB-1 proliferation rate and p53 positivity may aid in the prediction of disease stage

and disease progression, whereas polymerase chain reaction (PCR) testing can support

the diagnosis and reduce the number of histologically indeterminate lesions.[40]

Treatment & Management

Intraocular lymphoma

Because of the high recurrence rate and refractory nature of primary central nervous

system lymphoma with ocular involvement (PCNSLO), treatment is difficult.[15]However,

treatment of intraocular lymphoma underwent a significant advance with the introduction

of chemoradiation to the central nervous system (CNS) and ocular radiation.

Radiation (3500-4000 cGy) alone to the eyes and CNS gave high rates of initial response,

but patients usually succumbed to recurrent disease. With multimodality therapy,

including a boosted radiation dose (5000-10,000 cGy) to the spinal cord and intrathecal

methotrexate, vision can be improved and life can be prolonged, with some patients alive

at 9 years after treatment. In selected cases, patients with isolated ocular disease have

been treated with ocular radiation alone, with some longer-term survivors.[41, 42, 43]

Innovations in treatment include multiagent primary chemotherapy. This approach was

designed to reduce the radiation-associated cognitive defects that can occur in up to 40%

of patients older than 50 years. The regimen includes methotrexate and procarbazine,

vincristine, thiotepa, or both vincristine and cytarabine. Complete remission has been

seen for as long as 30 months.[41, 42, 43]

Radiotherapy for PCNSLO is highly effective, and complications are generally

acceptable. Complications of radiotherapy include cataract, dry eye, corneal ulcer,

neovascular glaucoma, radiation retinopathy, and optic neuropathy.[44, 45]In the absence of

a clear advantage to intravitreal chemotherapy, which involves repetitive injections and

associated risks, radiotherapy may still be the most appropriate first-line treatment in

most cases.[46]

Research is ongoing to determine if lower doses of local radiation are effective and still

reduce associated complications.

Orbital and adnexal lymphoma

The recommended therapy for stage IE tumors is radiotherapy, whereas disseminated

disease is treated with chemotherapy.[38]

Lymphoid tumors of the conjunctiva have traditionally been treated with local radiation

therapy. Some cases of conjunctival lymphoma were seen to spontaneously regress after

biopsy; hence, follow-up without radiation has been considered an option for patients

with mucosa-associated lymphoid tissue (MALT) lymphoma of conjunctival origin after

the pathologic diagnosis by biopsy.[47]Cryotherapy for certain conjunctival lymphomatous

tumors has been suggested because of fewer ocular and systemic complications and lower

cost.[48]

Radiotherapy alone is a highly effective modality in the curative management of primary

orbital lymphoma.[44]Bilateral orbital disease itself, in the absence of systemic disease, is

not an indication for chemotherapy.

Approximately 50% of orbital lymphomas are confined to the orbit at the time of

diagnosis. In such cases, where there is no evidence of systemic lymphoma, local orbital

low-dose (1500-3000 cGy) irradiation in fractionated doses is advised. High-grade

tumors may require up to 4000 cGy. Appropriate shielding of the globe (lens-sparing

technique) is recommended to minimize ocular complications of radiotherapy.[44]

In cases of massive orbital involvement, both chemotherapy and radiation therapy can be

simultaneously given.

Because secondary orbital lymphomas often exhibit widespread systemic involvement

and usually have a more aggressive histologic classification than primary orbital

lymphomas do, treatment of these lesions with systemic chemotherapy or systemic

immunotherapy is warranted. In some cases, combining such systemic therapy with local

radiation treatment is beneficial.[49]After radiotherapy, local control was achieved in 97-

100% of patients.[44, 50]

Lymphomas respond well to monoclonal antibody (mAb) therapy, and research is

ongoing to determine if such therapy can replace chemotherapy. Rituximab, ibritumomab,

and epratuzumab are examples of mAbs that either are already in use or are being tested

for use in lymphoma treatment. Intravenous rituximab has been used to treat low-grade

lymphoma, with good results.[51, 52]

Antiangiogenic drugs, such as thalidomide, are also being researched for use in

lymphoma treatment, as they are shown to slow the growth of cancer cells.

Consultations

Neurologic evaluation is required in patients with intraocular lymphoma to rule out CNS

involvement. Patients with ocular lymphoma should be referred to the clinical oncologist

for evaluation of systemic lymphoma.

Further outpatient care

Despite usually demonstrating an indolent course, extranodal marginal zone B-cell

lymphomas are renowned for recurrence in extranodal sites, including other ocular

adnexal sites.[38]These sites can also include the lung, parotid gland, and bone marrow.[45]

Close clinical follow-up every 6 months for 2 years upon completion of treatment and

annually thereafter is recommended. The evaluation should include neuroimaging studies

(eg, ultrasonography, computed tomography [CT], or magnetic resonance imaging [MRI]

of the orbits) to look for residual or recurrent local disease.

Serial imaging can be a very useful tool for detecting recurrence. Residual fibrosis of

involved extraocular muscles or other orbital structures can appear similar to tumor.

Whether re-biopsy or exploration is indicated should be a clinical decision, often aided by

serial imaging.

A clinical oncologist should also follow up with the patient for a thorough systemic

evaluation every 6 months for 2 years and annually thereafter.

Prognosis

Death can occur as a result of the systemic spread of lymphoma. [4]Prior or concurrent

systemic disease has been noted as the most significant predictive factor for lymphoma-

related death, but tumor-related death was also found to be more common and earlier

with bilateral disease. Tumor-related death is slightly less where symptoms have been

present for more than a year and slightly greater in the elderly.

Patients with primary central nervous system lymphoma with ocular involvement

(PCNSLO) have a poor prognosis even with chemoradiation, and many succumb to

central nervous system (CNS) disease within 2 years. Yet, median survival of primary

central nervous system lymphoma (PCNSL) has increased from 1-1.5 years to over 3

years with newer therapies. Features affecting the prognosis of PCNSLO are not well

understood.[53]Death ensues by CNS dissemination. Ocular lymphoma may be the initial

manifestation of PCNSL.

In a study of patients with ocular adnexal lymphomas, age, sex, and anatomic location of

the lymphomas did not have prognostic significance during a follow-up period of 6

months to 16.5 years.[40]The major prognostic criteria for ocular adnexal lymphomas

include anatomic location of the tumor, stage of disease at first presentation, subtype of

lymphoma, immunohistochemical markers determining factors such as tumor growth

rate, and the serum lactate dehydrogenase (LDH) level.[38]

The extent of disease at the time of presentation was the most important clinical

prognostic factor. Advanced disease correlated with increased risk ratios of having

persistent disease at the final follow-up and lymphoma-related death.[40]

The longest survival has been seen in patients with low-grade lymphomas (ie, marginal

zone lymphoma, follicular lymphoma).[54]However, T-cell lymphomas are associated with

high mortality with conventional treatment, as there is a high incidence of systemic

involvement.[55]

The overall prognosis for ocular adnexal lymphoid tumors is excellent; when lumped

together, 67% are not found to be associated with systemic disease with a mean follow-up

of over 4 years. Over the course of follow-up, it could be anticipated that 20-25% of

patients not known to have systemic lymphoma develop evidence of disseminated disease

within 5 years.[56]

Conjunctival lymphoma is known to have the lowest rate of extraorbital spread and

lymphoma-related death, the rate of these 2 events being sequentially greater for patients

with predominantly deep orbital lymphoma, lacrimal gland lymphoma, or eyelid

lymphoma.[57, 56]

With radiotherapy for orbital disease, the 5-year disease-free survival and overall survival

rate has been between 65-73.6% and 65.5-78%.[44, 50]Most relapses occur in the first 2

years after therapy. The risk of late relapse is higher in patients with a divergent histology

of both indolent disease and aggressive disease.

Intraocular lymphoma can lead to blindness due to damage of the intraocular structures

involved. Orbital lymphoma can cause blindness in untreated or aggressive cases with

severe proptosis leading to corneal complications or optic neuropathy. Local irradiation

can also cause reversible blindness due to cataract and irreversible blindness in cases of

radiation-induced optic neuropathy and retinopathy