Clinical and Translational Radiation Oncology 38 (2023) 15–20

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Clinical and Translational Radiation Oncology

journal homepage: www.sciencedirect.com/journal/clinical-and-translational-radiation-oncology

Radiation therapy for primary orbital and ocular adnexal lymphoma

Maria Valeria Pereira-Da Silva a, b, Maria Laura Di Nicola a, b, Filiberto Altomare a, b, Wei Xu d,
Richard Tsang c, Normand Laperriere c, Hatem Krema a, b, *
a
Ocular Oncology Service Princess Margaret Cancer Center/University Health Network, Canada
b
Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada
c
Radiation Oncology Department, Princess Margaret Cancer Center/University Health Network, Canada
d
Department of Biostatistics, Princess Margaret Cancer Center/University Health Network, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To report the efficacy and toxicity of External beam Radiotherapy (EBRT) as a sole treatment for MALT
Lymphoma and Follicular Primary Orbital and Ocular adnexal Lymphoma (POOAL)
Ocular adnexa Methods: Retrospective review of all POOAL patients treated with EBRT utilizing megavoltage photon or electron
Orbit
beam radiotherapy between 2003 and 2015. Patient demographics, tumour extent and pathology, radiotherapy
Periocular
Radiotherapy
techniques, and treatment outcomes were reviewed. The actuarial rates of tumour control and radiation toxicities
were calculated using Kaplan-Meier estimates.
Results: This study included 167 tumours, of which MALT lymphoma involved 149 (89 %). The conjunctiva and
orbit were equally involved as the predominant site (48 %). Megavoltage photon radiotherapy was used in 60 %
of predominantly orbital lymphoma and Electron beam with lens shielding in 77 % of the conjunctival lym­
phoma. The majority (95 %) were treated with a total dose of 25 Gy in 10 fractions. Local control rate was 98 %
(CI: 93–100 %) at 5 years. The long-term RT toxicities included dry eye in 27 eyes (16 %) and cataract in 22
(13 %). None of the patients developed significant structural or functional radiation toxicity.
Conclusion: External Beam Radiotherapy, with lens shielding whenever indicated, at a dose of 20–30 Gy delivered
over 10–20 fractions is an efficacious and safe primary treatment option for POOAL lymphoma, with excellent
local control and low incidence of late manageable ocular toxicities.

Introduction (MALT) is the most common histopathological type of periocular lym­

phoma [9–12]. Clinically, POOAL typically presents as a diffuse lesion
Lymphomas are a group of neoplasms that develop from B-lympho­ that involves one or more of the ocular adnexa and/or orbital structures.
cytes, T-lymphocytes, or NK lymphocytic cell origin[1,2]. The 4th edi­ Conjunctival involvement typically appears as slowly growing, infiltra­
tion of the WHO Classification of Tumors of Hematopoietic and tive, salmon-coloured lesion involving the conjunctival stroma and the
Lymphoid Tissues, published in 2017, classifies the lymphoid neoplasms underlying Tenon’s capsule (Fig. 1A). In the orbit, it may involve the
into 5 main categories: (1) Precursor lymphoid neoplasms; (2) Mature B- lacrimal gland, extra-ocular muscles, intra or extraconal spaces, or
cell neoplasms; (3) Mature T-cell neoplasms; (4) Hodgkin lymphoma; multiple periocular tissues (Fig. 1B–D). Orbital imaging reveals lym­
and (5) Immunodeficiency-associated lymphoproliferative disorders[3]. phoma as an ill-defined infiltrative mass that molds to the shape of
The incidence of lymphoma has increased considerably in the western surrounding structures[8]. This diffuse presentation excludes complete
countries over the last decades [4–6]. Brenner et al estimated in 2020, surgical excision as a suitable approach to cure extensive POOAL.
10,400 cases of non-Hodgkin lymphomas in Canada[7]. However, incision biopsy of the lesion is essential for diagnosis and
Primary Orbital and Ocular adnexal Lymphoma (POOAL) represents establishing a treatment plan.
8 % of all extra nodal lymphomas, and it is the most common primary Lymphoma treatment generally may include radiotherapy (RT),
orbital malignancy in adults[8]. Lymphomas involving the periocular chemotherapy, immunomodulating therapy, primary antibiotic treat­
tissue are in 90 % of cases of mature B-cell origin [3]. Extra nodal ment, surgical excision, or combination therapy. The choice of treatment
marginal zone B-cell lymphoma of mucosa associated lymphoid tissue depends on systemic staging and the tumor histopathologic type at the

* Corresponding author at: Ocular Oncology, Princess Margaret Cancer Centre/UHN, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
E-mail address: [email protected] (H. Krema).

https://doi.org/10.1016/j.ctro.2022.10.001
Received 24 August 2022; Received in revised form 3 October 2022; Accepted 5 October 2022
Available online 8 October 2022
2405-6308/© 2022 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.V. Pereira-Da Silva et al. Clinical and Translational Radiation Oncology 38 (2023) 15–20

Fig. 1. Salmon patch presentation of conjunctival MALT lymphoma (A), Axial view of CT scan demonstrating lacrimal gland enlargement secondary to orbital
lymphoma (B), Orbital lymphoma compromising extra-ocular muscles (C), clinical image of lymphoma involving the lacrimal gland (D). Electron beam radiation (E)
Pencil shield utilized to reduce lens dose during electron beam radiation (F).

Table 1 Table 3
Summary table stratified by Histology and site of tumor presentation. Summary table stratified by Histology and site of tumor with distant relapse.
Histology Conjunctiva Orbit Eyelid Total Histology Conjunctiva Orbit Eyelid Total
(48%) (48%) (4%)
MALT Lymphoma 9 16 1 26/149 (17%)
MALT Lymphoma 74 70 5 149 (89%) Follicular Lymphoma 1 2 0 3/18 (17%)
Follicular 8 10 0 18 (11%) Total 10 18 1 29/167 (17%)
Lymphoma
Total 84 84 6 167
(100%)
Table 4
Comparison of the outcomes of Ocular Adnexal MALT lymphoma with systemic
treatments.
Table 2
Summary table stratified by treatment. Study Treatment Type # of Local Median
Patients Control Follow-up
Covariate Full sample Electrons Photons (months)
(n=167) (n=54) (n=113)
Ferreri Doxicycline 100mg 9 22% 12
Gender et al., bid/3w
Female 107 (64%) 36 (67%) 71 (63%) 2005
Male 60 (36%) 18 (33%) 42 (37%) Ferreri Doxycycline 3 weeks 27 22% 14
et al.,
2006
Site
Ham et al., Doxicycline 100mg 90 65% 40.5
Conjunctiva 82 (49%) 40 (77%) 42 (37%)
2015 bid/3w
Eyelid 5 (3%) 2 (4%) 3 (3%)
Annibali Rituximab 6 cycles 7 67% 29
Orbit 80 (48%) 12 (23%) 68 (60%)
et al., 375mg/mq IV every 3
2015 weeks
Diagnosis
MALT Lymphoma 150 (86%) 48 (89%) 102 (90%)
Follicular Lymphoma 17 (10%) 6 (11%) 11 (10%) initial presentation. Since POOAL is mostly confined to the periocular
tissue, orbital RT has been mostly elected as a primary treatment. There
Shield is a lack of consensus about the optimal RT dose, and fractionation
No 88 (53%) 13 (24%) 75 (66%) scheme [13–15]. In this study, we present our RT protocol, clinical
Yes 79 (47%) 41 (76%) 38 (34%)
outcomes, and long-term toxicities of RT in the management of a large
cohort of MALT and Follicular POOAL.
Dose binary
High dose (>=2500 132 (79%) 20 (37%) 112 (99%)
Patients and methods
Gy)
Low dose (<2500 Gy) 35 (21%) 34 (63%) 1 (1%)
A retrospective electronic chart review was conducted for all
consecutive patients that were diagnosed with MALT and Follicular
POOAL and were treated with radiotherapy between December 2003
and October 2015 and followed afterwards at Princess Margaret Cancer

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M.V. Pereira-Da Silva et al. Clinical and Translational Radiation Oncology 38 (2023) 15–20

Table 5
Reports of radiotherapy outcome for orbital lymphoma.
Study Radiation Dose Type of Lymphoma # of Patients Local Control Median Follow-up (yrs) Toxicities

Fung et al., 2003 30.6 Gy MALT (57%) 98 100% 6.8 Cataract 16 (16%)
Follicular (15%) Retinopathy 4 (4%)
DLBCL (9%) Corneal perforation 1 (1%)
Other (12%)

Goda et al., 2010 65 pts 25 Gy MALT (100%) 71 99% 7.4 NS

5 pts, 25-30 Gy
1 pt, 35 Gy

Goda et al., 2011 87 pts, 25 Gy MALT (100%) 89 99% 5.9 Cataract 22 (25%)
2 pts, 36 Gy Dry Eye 22 (25%)
Keratitis 3 (3%)
Retinopathy 3 (3%)

Konig et al., 2016 45 pts, 36 Gy MALT (52%) 52 98.00% 9.9 Conjuntivitis 28 (54%)
7 pts, 4 Gy Follicular (15%) Dermatitis 24 (46%)
Immunocytoma (9%) Dry Eye 14 (27%)
Other (25%) Cataract 11 (21%)
Keratitis 1 (2%)
Corneal ulcer 1 (2%)

Ohga et al., 2015 30 Gy MALT 100% 73 100% 3.8 Cataract 31 (43%)

Dry Eye 22 (30%)
Keratitis 5 (7%)
Conjuntivitis 4 (6%)

Parikh et al., 2015 30.6 Gy MALT 75% 79 100% 4.1 Cataract 11 (14%)
Follicular (25%) Dry Eye 13 (17%)
Retinopathy 2 (3%)

Son et al., 2010 30.6 Gy MALT 100% 46 93% 2.7 Cataract 2 (4%)
Dry Eye 6 (13%)
Tearing 2 (4%)
Keratitis 2 (4%)

Stafford et al., 2001 27.5 Gy MALT (60%) 48 98% 5.4 NS

CLL (23%)
DLBCL 4%
Other 13%

Uno et al., 2003 36 Gy MALT 100% 50 98% 3.8 Conjuntivitis 8 (16%)

Cataract 6 (12%)
Keratitis 1 (2%)
Retinopathy 2 (4%)

Woolf et al., 2015 30 - 35 Gy MALT (88%) 81 100% 4.4 Cataract 6 (7%)

Follicular (6%) Dry Eye 3 (4%)
T-cell 1% Conjuntivitis 19 (24%)
B-precusor Lymphoblastic 1 % Erythema 19 (24%)
Other 4 (5%)

Centre/University Health Network, Toronto, ON, Canada. The study was structure (conjunctiva, orbit, eyelid). All included POOAL tumours were
conducted according to the declaration of Helsinki, and the institutional diagnosed with prior tissue biopsy and were analyzed with flow
research ethics board has approved it. Patients who presented with cytometry and/or immunohistochemistry. The histopathologic diag­
unilateral or simultaneous bilateral periocular involvement were nosis included: (MALT lymphoma and Follicular lymphoma). Treatment
included. Diagnosis of POOAL was based on clinical and/or orbital im­ description included: type of radiotherapy (electron beam radiotherapy
aging of the lesion, in addition to histopathologic confirmation. Patients or megavoltage photon beam radiotherapy), treatment total dose, frac­
with associated systemic lymphoma (i.e., stage III/IV disease) at pre­ tionation schedule, and the use of shielding of the crystalline lens during
sentation, who required primarily systemic treatment, were excluded. irradiation (used or not used). The acute treatment toxicities included,
Similarly, patients with incomplete pre-treatment or post treatment skin erythema, skin ulceration, telangiectasia, conjunctival hyperemia,
data, or less than 1-year follow-up were excluded. and corneal ulceration. The long-term toxicities included, radiation-
induced cataract, radiation retinopathy, persistent dry eyes, iris neo­
vascularization, and neovascular glaucoma. The terminology criteria for
Patient data
adverse events, version 3 (CTCAE v3.0), was used to record late
toxicities.
Patient data included: demographics (age at diagnosis date, gender,
and laterality of involvement), the predominantly involved adnexal

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M.V. Pereira-Da Silva et al. Clinical and Translational Radiation Oncology 38 (2023) 15–20

Radiation therapy Results

Selection of RT technique was individualized according to the extent Out of 314 POOAL patient charts reviewed, 140 patients with 167
of tissue involvement. Based on orbital imaging, Electron Beam Radio­ tumours met the inclusion criteria. There was no gender predilection
therapy was elected for localized eyelid and/or conjunctival lymphoma, and 112 patients (80 %) showed unilateral involvement. Clinically, the
not extending beyond the globe equator. Electrons energies are typically conjunctiva and the orbit were equally involved as the primary site.
12 MeV to 16 MeV and covers the entire orbit. Megavoltage photon The histopathology of the majority of lesions was MALT lymphoma
irradiation has been used for deeper lesions involving lacrimal gland, (89 %), followed by Follicular lymphoma (11 %). Table 1 summarizes
orbital soft tissue, extraocular muscles, or for bulky eyelid and the categorization of cases with respect to the histologic diagnosis and
conjunctival lesions that extended beyond globe equator. site of involvement.
Technique: on the treatment table, the patient head was immobilized All cases were treated either with Linear Accelerator (LINAC)- based
using a custom-fitted thermoplastic mask; a non-contrast computerized megavoltage photon radiotherapy or Electron beam radiotherapy as a
tomography (CT) imaging of the head was executed. The target volumes primary treatment. Table 2 demonstrates the choice of treatment as
(GTV where applicable, and the CTV) were contoured on the CT images, stratified according to the patient gender, tumour location, histologic
with addition of 3–5 mm margin for the PTV to account for possible day- diagnosis, the use of shielding, and radiation type. The majority (95 %)
to-day set-up errors. The planning images were then uploaded into the of patients were treated with photon irradiation at a standard dose of
planning software. Treatment planning was applied, where doses are 25 Gy or less in 10 fractions, 4 tumours were treated with 30 Gy, 3 in 20
calculated and isodose distributions and dose-volume histograms were fractions.
generated to the target volume and the nearby tissues. Image guidance The median follow-up, after radiotherapy, was 6.1 years (range,
was performed with cone beam-CT at each treatment session, and 1–20 years). The actuarial local control rate was 98 % (Confidence In­
coverage adjusted for any translation error in the X, Y, and Z dimensions. terval; CI: 96–100 %) at 3 years, and was 97 % (CI: 93–100 %) at 5 years.
Electron beam treatment (Fig. 1E) was delivered using direct ante­ Local recurrence was observed in only 6 tumors (3.6 %) of 4 patients. All
rior beam, while megavoltage irradiation was delivered over 3–5 fields, recurrent cases were MALT lymphoma, which were treated with the
through Intensity Modulated Radiotherapy (IMRT). A “Pencil Shield” standard photon irradiation (25 Gy/10 fractions); in two of these pa­
made of Tungsten alloy and a lead head, suspended at 1 cm from cornea, tients, lens shielding was used. Time to local recurrence varied from 14
was utilized to reduce lens dose during electron beam irradiation to 84 months after treatment. One patient with a large tumor showed no
(Fig. 1F). Lens shielding was used if the target volume was beyond 3 mm response.
from the limbus. Lesions within 3 mm from the limbus were treated Acute RT toxicities were observed in 80 % of patients, mainly as a
without lens shielding. mild degree of periorbital skin erythema, conjunctival injection, and
The standard dose of photon radiotherapy used for MALT lymphoma excessive tearing or chemosis immediately after RT, most of which were
was 25 Gy delivered in 10 fractions; few patients before 2005 were self-limited and responded to a short course of lubricant gels or skin
treated with 35–40 Gy in 20 fractions. In electron radiotherapy, with moisturizers.
relatively higher surface dose, the dose was 20 Gy in 10 fractions to The long-term RT toxicities included dry eye in 27 eyes (16 %) fol­
minimize ocular surface dryness. lowed by cataract in 22 eyes (13 %). Serious toxicities such as neo­
vascular glaucoma and radiation retinopathy were not observed in this
Follow-up cohort. The cumulative incidence at 5 years of dry eyes was 14 % (CI:
81–90 %) and of radiation induced unilateral cataract was 11 % (CI:
Patients were examined at 4 to 8 weeks after completion of radio­ 84–94 %). All long-term toxicities were treated with success, except for a
therapy, to assess the initial response to irradiation including manage­ patient with pre-existing Sjogren syndrome who developed severe dry
ment of short-term treatment toxicities. Subsequently, patients were eye.
followed every 3 months for the first year, then every 4 to 6 monthly for Development of systemic disease (distant relapse) has subsequently
2 years, then yearly thereafter. Follow-up assessment included occurred in 29 patients (20 %); 2 patients developed the disease in the
ophthalmic clinical examination for response of superficial lymphoma, contralateral untreated eye. The median time to distant relapse of
and 6 monthly orbital imaging with CT and/or magnetic resonance lymphoma was 36 months (1–152 months). The primary histologic
imaging (MRI) scans. Complete response was defined as complete res­ diagnosis of the patient with systemic relapse was MALT lymphoma in
olution of the local disease by physical examination and orbital imaging. 24 patients, Follicular lymphoma in 3 patients. Conjunctiva was affected
Treatment efficacy was measured as the rate of local tumour control in 10 patients, orbit in 19 and eyelid in 1 patient (Table 3).
versus local recurrence. Treatment failure was defined as local relapse Patients were treated according to histological diagnosis of the
within the irradiated region. The relapse patterns (local, contralateral relapse and stage of disease.
orbit, and distant systemic) and late toxicities were recorded based on
detailed ophthalmologic evaluation. Discussion

Statistical analysis Lymphoma is the most common primary malignant neoplasm of the
orbit [16]. In this study, POOAL has equally involved each of the con­
Survival distributions for the overall time- to- local failure, as well as junctiva and orbit as the primary periocular site, involving 48 % of the
proportion with local control, -based on treatment parameters such as eyes in each site.
radiation energy were calculated using Kaplan-Meier estimates. Rates of Extra nodal MALT lymphoma is the most frequent histologic subtype
complications were calculated using the cumulative distribution func­ of the ocular adnexal lymphoma with reported incidence ranging from
tion for overall time to various radiation complications and for time to 35 % to 90 %.[2,5,8] In this study MALT lymphoma represented 89 % of
complications aggregated by radiation type and energy level; with or the tumors of the entire cohort irrespective of the primary site of origin.
without shielding. Long rank test was used to compare the statistical This higher incidence probably reflects the selection criteria of the
significance between the survival curves. Results were considered sig­ included lymphoma patients in this study, who were treated solely with
nificant if the p-value was less than 0.05. orbital radiotherapy. MALT lymphoma is a low-grade lymphoma that
mostly presents as a unilateral periocular disease without concurrent
systemic involvement, the patients with higher-grade lymphoma and
systemic involvement at presentation, requiring treatments other than

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M.V. Pereira-Da Silva et al. Clinical and Translational Radiation Oncology 38 (2023) 15–20

RT, were not included. neovascular glaucoma, radiation retinopathy or ocular hemorrhage. A
MALT lymphoma has been reported to be associated with chlamydia possible reason could be due to reporting practice, as patients were
psittaci infection, which proposed the use of doxycycline as a treatment, followed in a dedicated eye clinic at the institution.
however the association between infectious disease and lymphoma Distant relapse is more frequent in more aggressive lymphomas as
showed geographic differences. The C psittaci strains found in Europe Large B-cell lymphomas. Although MALT lymphoma is a more frequent
and South Florida present genotypic variance that may explain the diagnosis it presents less distant relapse as well as the Follicular lym­
different results seen in the literature.[9,17,18] Local control varied phoma, 17 % in both cases. (Table 5).
from 22 % to 65 % when doxycycline was used to treat ocular adnexal
lymphoma [18–20] and with the use of Rituximab as sole agent in one Conclusion
study, the authors reported 65 % of local control [21] (Table 4). The
published RT series on treatment of MALT lymphoma revealed better Despite the retrospective nature of this study, yet it demonstrates the
control rates when compared to other treatments. efficacy and low toxicity of RT with a dose of 25 Gy achieved in a large
In patients with localized lymphoma, radiotherapy is usually the cohort of Low grade (MALT and Follicular) POOAL patients who were
treatment of choice. Radiotherapy is often used as primary treatment treated with the same technique and followed at the same institution.
alone for indolent lymphomas [22]. Nevertheless, there is a lack of Radiotherapy at a dose of 20–25 Gy fractionated in 10–15 sessions
consensus about the optimal RT type, dose, and fractionation scheme. with use of lens shielding whenever indicated is an efficacious and safe
[13] Even though the radiation dose required for eradication of disease option for Primary Orbital and Ocular Adnexal low-grade lymphoma
is low to moderate, the treatment of POOAL might be technically chal­ treatment, with excellent local control and low incidence of late
lenging considering the proximity to radiosensitive ocular structures. manageable ocular toxicities.
Megavoltage photon beam has been a standard therapy for a variety
of deeper orbital tumours. Use of IMRT in this study, aims at optimizing
energy delivery to the tumour-involved tissues whilst minimizing Declaration of Competing Interest
collateral tissue injury has been the mainstay approach. Conversely,
electron beam therapy is more applicable for superficial lymphoma The authors declare that they have no known competing financial
involving the eyelids and conjunctiva.[23]. In the latter situation, interests or personal relationships that could have appeared to influence
crystalline lens shielding has been used to minimize incidence of the work reported in this paper.
radiation-induced cataract. Therefore, tumor site and extent of orbital
involvement in the study has defined the selection of radiotherapy
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