Uveal Lymphoma: Clinical Features,

Diagnostic Studies, Treatment Selection,

and Outcomes
Mary E. Aronow, MD,1 Craig A. Portell, MD,2 John W. Sweetenham, MD,2 Arun D. Singh, MD1

Objective: To describe the clinical features, ancillary diagnostic studies, and treatment selection in a cohort
of patients with uveal lymphoma.
Design: Retrospective clinical review.
Participants: A total of 22 patients (34 affected eyes) diagnosed with uveal lymphoma between 1997
and 2013.
Methods: Data were collected regarding patient characteristics, clinical features on ophthalmic examination,
ancillary imaging studies, and primary treatment selection.
Main Outcome Measures: Relapse defined as lymphoma recurrence in the initial site of presentation, the
contralateral eye, or other systemic site and overall survival.
Results: Fifteen patients were male (68.2%). Median age at diagnosis was 68.0 years. The choroid was
involved in 21 cases (95.5%), and 1 case (4.5%) was ciliochoroidal. Other ocular adnexal structures were affected
in 13 patients (59.1%), including the conjunctiva in 4 (18.2%), the orbit in 7 (31.8%), and both the conjunctiva and
orbit in 2 (9.1%). Bilateral disease was present in 12 patients (54.5%). The most common presenting symptom
was decreased vision in 15 patients (68.2%). The median delay in diagnosis was 4.0 months. Yellow-white
choroidal infiltrates were observed on fundus examination in 34 eyes (100.0%) with corresponding hypofluor-
escence in 100% of cases when indocyanine green angiography was performed. Infiltrates were located anterior
to the arcades (67.6%), most commonly in a diffuse (32.4%) or superotemporal (32.4%) distribution. B-scan
ultrasonography detected extrascleral extension in 22 patients (75.9%) with a pattern of crescentic thickening in
19 (86.4%). Extranodal marginal zone lymphoma was the predominant (76.2%) histologic subtype. External beam
radiotherapy (72.7%) was most commonly chosen for primary treatment. Systemic imaging at the time of
diagnosis revealed that the majority of cases (77.3%) were localized to the eye; none of the patients developed
new systemic disease (median follow-up, 30.3 months).
Conclusions: Uveal lymphoma has distinctive clinical features. Overlap with ocular adnexal structures is
common, and ancillary imaging is essential for evaluating the full extent of ocular disease and presence of
systemic involvement. Ophthalmology 2014;121:334-341 ª 2014 by the American Academy of Ophthal-
mology.

Uveal lymphoma is typically a noneHodgkin’s lymphoma,
most frequently of B-cell origin. It can be classified as
primary uveal lymphoma or a secondary intraocular mani-
festation of systemic lymphoma. Primary uveal lymphoma
can be further subdivided into choroidal, iridal, and ciliary
body lymphoma. Primary choroidal lymphoma accounts for
the majority of cases and is generally a low-grade lymphoma
with a prolonged, benign course. In general, uveal lymphoma
has a high response rate to various treatment modalities,
including radiation, monoclonal antibodies, and chemo-
therapy.1 Histopathologically, uveal lymphoma may be one
of several subtypes; extranodal marginal zone B-cell
lymphoma (EMZL) is the predominant form, comprising
60% to 80% of cases.2,3 The incidence of primary iridal
and ciliary body lymphoma is unknown because these
malignancies have been described in only a handful of case
reports. Although primary choroidal lymphoma is rare, it
accounts for approximately 70 to 80 case reports and small
case series in the literature.4e6
The differential diagnosis of uveal lymphoma is broad
and includes diffuse or amelanotic uveal melanoma, uveal
effusion syndrome, posterior scleritis, uveal metastases, and
various uveitities, such as sarcoidosis and birdshot cho-
rioretinopathy. Because many ophthalmic diseases can
mimic uveal lymphoma, patients frequently go undiagnosed
for extended periods before establishment of the correct
diagnosis and proper initiation of treatment.7e11 In regard to
initial diagnoses, a strong correlation has been observed
between uveal lymphoma and coexisting ocular adnexal
lymphoma (OAL).12e17 This is logical in light of the fact

334  2014 by the American Academy of Ophthalmology ISSN 0161-6420/14/$ - see front matter
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2013.09.004
 Aronow et al 
Uveal Lymphoma: Features, Diagnostics, Treatment, and Outcomes
that the 2 diseases behave similarly from a clinical stand-
point and that they are often identical histomorphologically.
Uveal lymphoma may in fact be more accurately classified
as a variant of OAL.12
The purpose of the present retrospective study was to
identify diagnostic clinical features and findings of ancillary
imaging and diagnostic studies that aid in timely diagnosis
and to report trends in primary treatment selection and
outcomes.
Methods
A total of 22 patients (34 affected eyes) were diagnosed with uveal
lymphoma at the Cleveland Clinic between November 1997 and
May 2013. The diagnosis was established in 21 of 22 patients
(95.5%) by tissue biopsy that was performed at the Cleveland
Clinic or reviewed by a Cleveland Clinic staff pathologist when
biopsy was performed elsewhere. This study was approved by the
Cleveland Clinic Institutional Review Board. All research adhered
to the tenets of the Declaration of Helsinki. Eleven of the patients
in this series have been reported in a larger series of patients with
OAL.17 This previous work focused on the assessment of a tumor,
node, metastasis staging system for patients with OAL and
highlighted the finding that a significant percentage (15.9%) have
coexisting uveal lymphoma.
Data were collected regarding clinical features, including
patient age at diagnosis, gender, and extent of lymphoma
involvement (affected components of the uveal tract and overlap
with ocular adnexal structures and laterality). This was accom-
plished by complete ophthalmic examination, including measure-
ment of visual acuity, intraocular pressure, pupillary reflex testing,
external inspection for regional lymph node involvement, exoph-
thalmometry, ocular motility testing, slit-lamp examination, and
dilated fundus examination. In addition, historical aspects relating
to the presentation of uveal lymphoma in each patient were
reviewed. These included the initial symptoms, previous diagnoses
and treatments before establishment of the diagnosis of uveal
lymphoma, and duration of delay in the diagnosis. The pattern of
uveal involvement (e.g., discrete infiltrates, plaquoid infiltrates,
choroidal thickening), location within the fundus, and predomi-
nantly affected quadrant(s) were recorded.
Diagnostic studies included ancillary imaging, biopsy, and
histopathology. A combination of imaging studies were analyzed.
B-scan ultrasonography was used to detect extrascleral extension
(ESE), which when present appeared as crescentic thickening just
posterior to the sclera or as a discrete mass. The findings of fluo-
rescein angiography (FA), indocyanine green angiography (ICG),
and neuroimaging with computed tomography (CT) or magnetic
resonance imaging (MRI) of the brain and orbits also were
analyzed. The method of biopsy was noted: fine-needle aspiration
biopsy, incisional, or excisional. The biopsy location (ocular or
extraocular) also was recorded. The lymphoma histologic subtype
was identified on the basis of histomorphology, immunohisto-
chemistry, or genotyping.
Data also were collected related to the selection of primary
therapy in each case. Patients were treated with one of several
modalities, including external beam radiotherapy (EBRT), ritux-
imab, or combination chemotherapy with rituximab, cyclophos-
phamide, doxorubicin, vincristine, and prednisone (RCHOP).
To screen for coexisting systemic lymphoma at the time of
diagnosis, all patients were referred to an experienced medical
oncologist at the Cleveland Clinic Taussig Cancer Institute for
initial staging studies at the time of diagnosis. These included
imaging with CT scan of the neck, chest, abdomen, and pelvis, and
in some cases, a positron emission tomography scan. Blood work,
including a complete blood count and complete metabolic panel,
was performed in all cases. Additional hematologic studies and
ancillary testing, such as bone marrow biopsy, were performed at
the discretion of the treating oncologist. Patients were followed in
an ophthalmic oncology clinic and by their medical oncologist
every 6 to 12 months (median follow-up, 30.3 months). In addition
to clinical examination, systemic surveillance with the previously
mentioned imaging studies was performed to monitor for disease
relapse. Relapse was defined as lymphoma recurrence in the initial
site of presentation, the contralateral eye, or other systemic site.
Results
Clinical Features
A total of 22 patients (34 affected eyes) were diagnosed with uveal
lymphoma between November 1997 and May 2013 at the Cleve-
land Clinic, Cole Eye Institute. The majority were male: 15 patients
(68.2%). The median age at diagnosis was 68.0 years (range,
46e85 years). One patient had a history of systemic follicular
lymphoma; the majority (95.5%) represented cases of primary
uveal lymphoma. Staging studies at the time of initial diagnosis
revealed that 5 patients (22.7%) had extraocular systemic disease.
None of the patients developed new systemic disease on surveil-
lance studies after a median follow-up of 30.3 months. Twenty-one
cases (95.5%) affected only the choroid. In a single case (4.5%),
both the choroid and ciliary body were involved. There were no
individuals with iris or ciliary body lymphoma. Overlapping
involvement with ocular adnexal structures was observed in 13
patients (59.1%). Coexisting uveal and orbital disease was present
in 7 patients (31.8%), uveal and conjunctival disease was present in
4 patients (18.2%), and uveal, conjunctival, and orbital disease was
present in 2 patients (9.1%). Bilateral involvement was observed in
12 patients (54.5%), the right eye alone was affected in 4 patients
(18.2%), and the left eye alone was affected in 6 patients (27.3%)
(Table 1).
Patients presented with a wide range of symptoms, the most
common of which was decreased vision, reported in 15 cases
(68.2%). Other frequent presenting symptoms included conjunc-
tival erythema in 4 patients (18.2%) and elevated intraocular
pressure (IOP) in 3 patients (13.6%). Orbital fullness was reported
in 2 patients (9.1%), and metamorphopsia was reported in 1 patient
Table 1. Clinical Features: Patient Characteristics and Site
of Involvement (22 Patients)
Gender
Male 15 (68.2%)
Female 7 (31.8%)
Median Age at Diagnosis 68.0 yrs (range, 46e85 yrs)
Uveal Involvement
Choroid 21 (95.5%)
Choroid þ ciliary body 1 (4.5%)
Ciliary body 0 (0.0%)
Iris 0 (0.0%)
Overlap with Ocular Adnexal Structures
Uvea only 9 (40.9%)
Uvea þ orbit 7 (31.8%)
Uvea þ conjunctiva 4 (18.2%)
Uvea þ conjunctiva þ orbit 2 (9.1%)
Laterality
Bilateral 12 (54.5%)
Right 4 (18.2%)
Left 6 (27.3%)
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 Ophthalmology Volume 121, Number 1, January 2014

Table 2. Clinical Features: Symptoms, Prior Diagnoses, and thickening was present in 16 eyes (47.1%), choroidal folds were
Previous Treatments (22 Patients) present in 4 eyes (11.8%), and plaquoid infiltrates were present
in 2 eyes (5.9%). The fundus location of these findings was
Symptoms (>1 possible) typically anterior to the arcades, present in 23 eyes (67.6%).
Decreased vision 15 (68.2%) These features were located in the posterior pole in 18 eyes
Conjunctival erythema 4 (18.2%) (52.9%) and along the arcades in 15 eyes (44.1%). The
Elevated IOP 3 (13.6%) predominant distribution was diffuse (involving all 4 quadrants)
Orbital fullness 2 (9.1%) in 11 eyes (32.4%), and a superotemporal distribution was
Metamorphopsia 1 (4.5%)
observed in 11 eyes (32.4%) (Table 3).
Asymptomatic 2 (9.1%)
Prior diagnoses (>1 possible)
Conjunctivitis 1 (4.5%) Diagnostic Studies
Epibulbar dermoid 1 (4.5%)
Scleritis 4 (18.2%) B-scan ultrasonography was performed in 29 of 34 eyes (85.3%).
Metastases 1 (4.5%) Extrascleral extension was detected in 22 eyes (75.9%) (Fig 2). The
CSR 1 (4.5%) ultrasonographic pattern of ESE was crescentic thickening in 19
Sarcoid 1 (4.5%) eyes (86.4%), and a discrete mass was present in 10 eyes
Birdshot chorioretinopathy 1 (4.5%) (45.5%). Additional ultrasonographic features included diffuse
Choroidal detachment 1 (4.5%) choroidal thickening in 18 eyes (62.1%) and subretinal fluid in 3
Vitreoretinal lymphoma 1 (4.5%) eyes (10.3%). Ultrasonography was normal in 6 eyes (20.7%) and
Secondary glaucoma 2 (9.1%) was not performed in 5 eyes (14.7%). Fluorescein angiography
Pseudotumor 1 (4.5%) was performed in 14 of 34 affected eyes and demonstrated early
Benign orbital tumor 1 (4.5%) hyperfluorescence in 11 eyes (78.6%), choroidal folds in 5 eyes
None 8 (36.4%)
(35.7%), and hypofluorescent spots corresponding to the clinically
Previous treatments (>1 possible)
observed choroidal infiltrates in 3 eyes (21.4%). Fluorescein
NSAIDs 1 (4.5%)
Topical steroid 5 (22.7%)
angiography was normal in 1 affected eye (7.1%). Indocyanine
Oral steroid 2 (9.1%) green angiography was performed in 21 affected eyes and
Periocular steroid injection 1 (4.5%) revealed hypofluorescent lesions corresponding to the clinically
Anti-VEGF injection 1 (4.5%) observed choroidal infiltrates in all cases (100.0%). Computed
Topical antibiotic 1 (4.5%) tomography of the brain and orbits was performed in 6 patients (7
Topical glaucoma therapy 2 (9.1%) eyes with ESE detected by B-scan ultrasonography), and the
Laser trabeculoplasty 1 (4.5%) presence of ESE was observed on CT in only 4 eyes (57.1%). In
Trabeculectomy 1 (4.5%) contrast, MRI of the brain and orbits was performed in 12 cases
Focal laser 1 (4.5%) (10 eyes with ESE detected by B-scan ultrasonography), and ESE
Vitrectomy 1 (4.5%) was observed in 7 eyes (70.0%) (Table 4).
None 13 (59.1%) Tissue biopsy was performed in all but 1 case. An extraocular
Median delay in diagnosis 4.0 mos (range, 0e24 mos) site (e.g., a peripheral lymph node) was selected in 3 of the 5
patients with systemic involvement detected at the time of
CSR ¼ central serous retinopathy; IOP ¼ intraocular pressure; NSAID ¼
nonsteroidal anti-inflammatory drug; VEGF ¼ vascular endothelial growth Table 3. Clinical Features (34 Eyes, 22 Patients)
factor.
Median BCVA at diagnosis 0.18 logMAR (range, 0.0e1.0)*
Uveal features (>1 possible)
(4.5%). Two patients (9.1%) were asymptomatic. Before biopsy Yellow-white infiltrates 34 (100.0%)
confirmation of uveal lymphoma, patients were diagnosed with Discrete infiltrates 31 (91.2%)
a number of masquerading conditions. The most common of these Diffuse thickening 16 (47.1%)
was scleritis in 4 patients (18.2%). Other diagnoses before referral Choroidal folds 4 (11.8%)
to our ophthalmic oncology clinic included conjunctivitis, epi- Placoid infiltrates 2 (5.9%)
bulbar dermoid, metastases, central serous retinopathy, sarcoid, Location in fundus (>1 possible)
glaucoma, pseudotumor, and benign orbital tumors. Slightly more Anterior to arcades 23 (67.6%)
than one-third, 8 cases (36.4%), were referred with an unknown Posterior pole 18 (52.9%)
disease. Individuals received an array of treatments before being Along arcades 15 (44.1%
diagnosed with lymphoma, including steroids in 8 patients: topical Predominant quadrant(s) involved
in 5 (22.7%), oral in 2 (9.1%), and periocular in 1 (4.5%). Other All/diffuse distribution 11 (32.4%)
Superotemporal 11 (32.4%)
reported therapies were anti-vascular endothelial growth factor
Superonasal 7 (20.6%)
injection, topical antibiotics, topical glaucoma drops, laser trabe-
Inferior temporal 4 (11.8%)
culoplasty, trabeculectomy, focal laser, vitrectomy, and nonste- Nasal 4 (11.8%)
roidal anti-inflammatory drugs. Thirteen patients (59.1%) received Temporal 3 (8.8%)
no treatment before referral. The median delay in diagnosis was 4.0 Superior 2 (5.9%)
months (range, 0e24 months) (Table 2). Inferior 2 (5.9%)
On examination, the median best-corrected visual acuity at the Inferonasal 1 (2.9%)
time of diagnosis was 0.18 logarithm of the minimum angle of
resolution (range, 0.0e1.0), corresponding to a Snellen visual
acuity of 20/30 (range, 20/20e20/200). The dominant fundus BCVA ¼ best-corrected visual acuity; logMAR ¼ logarithm of the
minimum angle of resolution.
finding was yellow-white choroidal infiltrates (Fig 1). These were
*Corresponds to median Snellen visual acuity of 20/30 (range, 20/20e20/
observed in 34 affected eyes (100.0%). The infiltrates were 200)
predominantly discrete in 31 eyes (91.2%). Diffuse choroidal

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Uveal Lymphoma: Features, Diagnostics, Treatment, and Outcomes

Figure 1. Discrete yellow-white choroidal infiltrates in the right eye of an 82-year-old woman with uveal lymphoma (A, B). Indocyanine green angiography
demonstrates a characteristic pattern of focal hypofluorescence corresponding to the clinically observed choroidal infiltrates (C). B-scan ultrasonography
revealed choroidal thickening (maximal elevation 1.6 mm) in the macula (D).

diagnosis. In total, extraocular biopsy was performed in 13.6% of
patients. The remaining patients underwent ocular biopsy of the
orbit (8 [36.4%]), the conjunctiva (7 [31.8%]), the choroid (2
[9.1%]), and the ciliary body (1 [4.5%]). The method of ocular
biopsy was incisional in 16 patients (88.9%), and fine-needle
aspiration biopsy was performed in 2 patients (11.1%). Extra-
nodal marginal zone lymphoma (EMZL) was the predominant
histologic lymphoma subtype (Figs 3 and 4, available at http://
aaojournal.org) and was found in 16 patients (76.2%). There was
1 case (4.8%) of follicular lymphoma and 1 case (4.8%) of low-
grade lymphoma not otherwise specified. In 3 patients (14.3%)
in whom ocular biopsy was performed, histopathology was non-
diagnostic. In these instances, the ocular site biopsied was the
conjunctiva, ciliary body, and orbit in 1 case each (Table 5).

Figure 2. A 58-year-old man with orbital congestion had been previously diagnosed with pseudotumor and treated with oral steroids. Fundus examination of
the left eye revealed yellow-white choroidal infiltrates (A). B-scan ultrasonography showed ESE in the form of crescentic thickening and a small mass near
the optic nerve (B). Incisional biopsy of the orbital mass revealed extranodal marginal zone lymphoma.

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 Ophthalmology Volume 121, Number 1, January 2014

Treatment Selection therapy (Table 6). None of the patients in our cohort died of
lymphoma-related complications.
Primary treatment selections included EBRT, rituximab, or
RCHOP. The majority of patients (16 [72.7%]) underwent treat-
ment with EBRT (Fig 5, available at http://aaojournal.org). These
were all patients who had only ocular disease. The median dose Discussion
of radiation was 3060 cGy (range, 2340e3600 cGy). A total of
5 patients (22.7%) were treated with rituximab with a median of Clinical Features
4 cycles (range, 4e12 cycles) (Fig 6, available at http://
aaojournal.org). One individual had widespread systemic disease Uveal lymphoma has distinct clinical features and, when
and was treated with RCHOP chemotherapy at an outside detected early, facilitates timely initiation of treatment. The
institution. male predominance (68.2%) with a median age of diagnosis
of 68.0 years (range, 46e85 years) is consistent with
previously published data.5,18,19 The dominant finding on
Outcome ophthalmic examination of yellow-white choroidal infil-
Treated individuals, regardless of modality, achieved complete trates was observed in 100% of 34 affected eyes. It is
remission in 78.6% of cases after a median follow-up of 30.3 important to emphasize the frequency of overlapping
months (range, 7.8e180.2 months). All patients (100%) with involvement with ocular adnexal structures present in 59.1%
localized disease treated with EBRT achieved complete remission of patients in this series and reported in other studies.12e17
(median follow-up, 28.7 months). A state of stable/asymptomatic In a series of 63 patients with primary OAL, we also
disease was achieved in 1 patient (10 months follow-up) and partial observed that 10 (15.9%) had coexisting uveal lymphoma17;
remission in 2 patients (median follow-up of 19.7 months). All 3 therefore, it is imperative to perform a complete ophthalmic
patients with stable disease or partial remission were in the ritux- examination (including dilated fundus examination) to
imab treatment group and received a total of 4 cycles as initial
exclude the possibility of uveal involvement in cases of
Table 4. Diagnostic Studies: Ancillary Imaging (34 Eyes, OAL. This is particularly relevant in patients with
22 Patients) suspected localized disease (e.g., conjunctival lymphoma),
in whom complete examination and ancillary imaging may
B-scan ultrasonography detect occult disease elsewhere. Characterizing the extent
Presence of ESE* 22 (75.9%) and laterality of disease has important staging and
Crescentic thickening 19 (86.4%)
treatment implications.
Discrete mass 10 (45.5%)
Choroidal thickening 18 (62.1%) This study emphasizes the variety of symptoms and
SRF 3 (10.3%) masquerading conditions in patients with uveal lym-
Normal 6 (20.7%) phoma.7e11 This was true in 12 patients (63.6%) in our series.
Not performed 5 (14.7%) Many individuals are initially treated with steroids, laser,
Angiography glaucoma medications, surgery, and other therapies before the
Fluoresceiny
diagnosis is established. This results in delay of diagnosis and
Early hyperfluorescence 11 (78.6%)
Choroidal folds 5 (35.7%) treatment (up to 2 years in our study).
Hypofluorescent lesions 3 (21.4%)
Normal 1 (7.1%)
ICGz Diagnostic Studies
Hypofluorescent lesions 21 (100.0%)
Neuroimaging
Because of the rare nature of this disease, limited informa-
CT brain/orbitx tion exists regarding the typical features observed on diag-
ESE detected 4 (57.1%) nostic studies.5,7,8,18e21 Imaging is critical for the detection
MRI brain/orbitk of extraocular involvement; however, the precise incidence
ESE detected 7 (70.0%) in which coexisting systemic lymphoma is present at the
Systemic disease status (presence of time of ocular diagnosis is unknown. The importance of
extraocular disease)
initial staging based on both clinical examination and
At diagnosis{ 5 (22.7%)
Surveillance# n ¼ 0 (0.0%) comprehensive diagnostic imaging is highlighted. Although
the eye was the site of presentation in all 22 patients, 5
patients (22.7%) had detectable systemic disease at the time
CT ¼ computed tomography; ESE ¼ extrascleral extension; ICG ¼
indocyanine green angiography; MRI ¼ magnetic resonance imaging; of diagnosis (of these, 1 patient had a known history of
SRF ¼ subretinal fluid. systemic follicular lymphoma). These rates are similar to
*ESE detected by B-scan ultrasonography. those described by Coupland et al.5 In their study, 1 patient
y
FA performed in 14 of 34 affected eyes. (7.7%) had detectable pulmonary disease at the time of
z
ICG performed in 21 of 34 affected eyes.
x
CT brain/orbit performed in 6 patients (7 eyes with ESE).
ocular diagnosis and 2 additional patients (15.4%)
k
MRI brain/orbit performed in 12 patients (10 eyes with ESE). developed systemic disease after 3 and 7 years of follow-
{ up. Detection of extraocular disease has important
Systemic status at diagnosis: based on CT (neck, chest, abdomen, pelvis)
or positron emission tomography scan, and complete blood count and management implications. Biopsy of an ocular site can be
metabolic panel. challenging because of the small amount of tissue available
#
Surveillance: performed every 6e12 months with the mentioned studies
(median follow-up, 30.3 months). for sampling and the potential for associated surgical
morbidity. When extraocular disease is present (e.g.,

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Uveal Lymphoma: Features, Diagnostics, Treatment, and Outcomes

Table 5. Diagnostic Studies: Biopsy and Histopathology useful particularly for further characterizing orbital lesions.
(22 Patients) Magnetic resonance imaging offers higher resolution and
superior visualization of soft tissue than CT and is therefore
Biopsy site
Extraocular* 3 (13.6%)
the preferred neuroimaging modality for this disease.
Orbit 8 (36.4%) Computed tomography of the orbits detected only 57.1% of
Conjunctiva 7 (31.8%) eyes with ESE evident on B-scan ultrasonography, in
Choroid 2 (9.1%) comparison with MRI, which detected 70.0% of these cases.
Ciliary body 1 (4.5%) Biopsy remains the gold standard for definitive diag-
Not performed 1 (4.5%) nosis. More recent techniques, including immunohisto-
Biopsy type (ocular)
Incisional 16 (88.9%)
chemistry, flow cytometry, and polymerase chain reaction
FNAB 2 (11.1%) gene rearrangement studies, have allowed for more accurate
Histopathologic diagnosis diagnosis.23e25 Many cases previously classified as benign
EMZL 16 (76.2%) reactive lymphoid hyperplasia (BRLH) are now considered
Follicular 1 (4.8%) malignant lymphoma using current diagnostic techniques.25
Othery 1 (4.8%) Retrospective studies of patients diagnosed with BRLH
Nondiagnostic 3 (14.3%)
have shown that up to 80% of these cases would now be
classified as malignant lymphoma.25 At present, BRLH
EMZL ¼ extranodal marginal zone lymphoma; FNAB ¼ fine-needle represents a minority of cases and is a diagnosis of
aspiration biopsy. exclusion. In the present series, of 21 patients who
*Extraocular: peripheral lymph node.
y
Other: benign reactive lymphoid hyperplasia. underwent biopsy and had characteristic clinical findings,
only 1 case was consistent with BRLH. The majority,
were low-grade EMZL or follicular lymphoma in 16 cases
(76.2%) and 1 case (4.8%), respectively.
a peripheral lymph node), this site is often advantageous for An additional challenge encountered in ocular biopsy is
biopsy. that the small amount of tissue obtained is sometimes
Ancillary imaging plays an important role in character- inadequate for diagnosis. This is particularly true when
izing disease extent. When performed, B-scan ultrasonog- structures such as the ciliary body are biopsied, and there-
raphy revealed ESE in 75.9% of cases, the most common fore only a small sample is removed because the risk of
pattern being crescentic thickening outside the posterior morbidity is high. In our series, 3 cases (14.3%) were
scleral margin. This finding was present many times in the nondiagnostic.
fellow eye where there was clinically unsuspected involve-
ment. In fact, B-scan ultrasonography was normal in only
20.7% of eyes, which highlights the sensitivity of this
imaging tool in detecting occult choroidal thickening and Treatment
ESE. Optimal treatment algorithms for uveal lymphoma have not
Angiography also is useful for characterizing disease been established because of the small number of patients
extent and laterality. Indocyanine green angiography with this disease and lack of long-term follow-up. In many
revealed a characteristic pattern of focal regions of hypo- institutions, EBRT has been the most frequently used
fluorescence corresponding to the clinically observed modality for localized uveal lymphoma, whereas chemo-
choroidal infiltrates. These foci may represent regions of therapy and immunotherapy have been reserved for patients
choroidal nonperfusion secondary to space-occupying with multifocal or systemic disease.14,26,27 External beam
lymphoma cells. Indocyanine green angiography is supe- radiotherapy for ocular lymphoma is based on lymphoma
rior to FA in visualizing the choroidal circulation and is grade, with indolent lymphomas generally receiving total
therefore particularly useful in confirming the diagnosis. doses of 2800 to 3600 cGy and higher grades receiving
When performed, FA yielded less reproducible findings than 3000 to 4000 cGy.14,26,27
ICG, consistent with the results of other reports that suggest At the Cleveland Clinic, the general treatment algorithm
that ICG is the preferred form of angiography for uveal for low-grade uveal lymphoma has been to treat those with
lymphoma.22 ocular-only disease with EBRT and those with bilateral,
Neuroimaging, although less sensitive than B-scan multifocal ocular-only disease (involving the uvea and
ultrasonography in detecting smaller regions of ESE, is extensive orbital involvement) or systemic disease with
single-agent rituximab. In the present series, EBRT was the
Table 6. Treatment: Selection of Therapy (22 Patients)
most frequent modality selected for primary treatment in 16
EBRT 16 (72.7%) patients (72.7%). Rituximab was administered in 5 cases
Median dose 3060 cGy (range, 2340–3600 cGy) (22.7%) and given in 4 cycles in 4 patients (induction only)
Rituximab 5 (22.7%) and in 12 cycles in the fifth patient (4 cycles of in-
Median cycles 4 (range, 4–12) duction followed by maintenance therapy) because of
RCHOP 1 (4.5%) recommendations in a recently published study.28
Chemotherapy with RCHOP was selected for only 1
EBRT ¼ external beam radiotherapy; RCHOP ¼ rituximab, cyclophos- patient (4.5%) with widespread systemic disease who was
phamide, doxorubicin, vincristine, prednisone. treated at an outside institution.

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 Ophthalmology Volume 121, Number 1, January 2014
Outcome
Uveal lymphoma is most frequently low grade; therefore, the
clinical course is often less aggressive than in other forms of
lymphoma.6 Regardless of the form of primary treatment,
individuals had good outcomes, achieving complete
remission in 78.6% of cases after a median follow-up of
30.3 months (range, 7.8e180.2 months). All patients with
localized disease treated with EBRT with a median dose of
3060 cGy (range, 2340e3600 cGy) achieved complete
remission (median follow-up, 28.7 months). Other reports of
uveal lymphoma treated with an EBRT dose of 3500 cGy
also have resulted in complete remission.6 The remainder of
patients in our series achieved a state of stable/asymptomatic
disease in 1 patient (10 months follow-up) and partial
remission in 2 patients after a median follow-up of 19.7
months. All 3 patients with stable disease or partial remission
were in the rituximab treatment group and received a total of
4 cycles as initial therapy. Although comparative studies
pertaining to the treatment of uveal lymphoma with rituximab
are not available, distant relapse rates of 50% have been
observed when rituximab is used as monotherapy for treat-
ment of OAL.29 None of the patients in our cohort died of
lymphoma-related complications. A detailed analysis of
treatment outcomes based on selection of therapy is beyond
the scope of this study because of the limited number of
patients included in the present cohort.
In conclusion, uveal lymphoma has distinct clinical
features that aid in timely diagnosis and initiation of treat-
ment. The frequently observed overlap between uveal
lymphoma and seemingly localized OAL (e.g., conjunctival
lymphoma) underscores the importance of complete and
bilateral ophthalmic examination, including dilated fundus
examination. Ancillary imaging also is important, particu-
larly bilateral B-scan ultrasonography, in detecting occult
ESE. Biopsy remains the gold standard in the definitive
diagnosis, which in most cases reveals a low-grade EMZL
subtype. Although treatment outcomes were favorable in the
majority of our cases, data on a large number of cases are
required to make firm conclusions regarding treatment
guidelines for uveal lymphoma.
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Footnotes and Financial Disclosures

Originally received: February 28, 2013. Supported in part through an unrestricted grant from Research to Prevent
Final revision: August 8, 2013. Blindness, Department of Ophthalmology, Cleveland Clinic, Lerner
Accepted: September 5, 2013. College of Medicine (ADS).
Available online: October 21, 2013. Manuscript no. 2013-320.
Correspondence:
1
Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Arun D. Singh, MD, Department of Ophthalmic Oncology, Cole Eye
Clinic, Cleveland, Ohio. Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-
2
Department of Hematologic Oncology and Blood Disorders, Taussig mail: singha@ccf.org.
Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials
discussed in this article.

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