Orbital lymphoma is rare and accounts for <1% of all cases of non-Hodgkin’s lymphoma. Most institutional reports had limited numbers of patients . Various subsites within the orbit may be involved, including the conjunctiva, lacrimal apparatus, eyelids, and musculature. Early-stage orbital lymphoma is best treated with radiotherapy (RT). In a study by Esik, the 10-year local relapse-free survival and 20-year cause-specific survival rates were 100%, 0%, and 42% and 100%, 67%, and 0%, respectively, for patients primarily treated with RT, surgery, or chemotherapy. The purpose of the present report was to review the efficacy of RT on early-stage primary orbital lymphoma as given in our institution and to determine the late effects and complications after treatment.

Treatment characteristics

All patients were treated with curative intent using external beam RT alone after biopsy of the lesion. Treatments were given 5 d/wk using a fraction size of 200 cGy in 36 orbits, 180 cGy in 15, and 170 cGy in 1. For low-grade lymphomas, the median dose was 3000 cGy (range 2000–4020); for the intermediate- and high-grade tumors, the median dose was 4000 cGy (range 3000–5100). Beam energy was 4-mV photons in 34 (65%), 6 mV in 6 (12%), 1.25 mV in 4 (8%), 10 mV in 3 (6%), and orthovoltage RT in 2 (4%). Electron beam RT was used in 3 patients (6%). The 2 patients who received kilovoltage RT were treated during the earlier part of the study. A lens-sparing approach was used in 19 (37%) of the orbits treated. Six patients were treated with parallel-opposed lateral fields; five had bilateral lymphoma and one had lymphoma and contralateral atypical hyperplasia of the orbit. The lenses of the 6 patients were spared from RT by using a half-beam block technique centered at the outer fleshy canthus of the eyes. The other eight orbits treated with a lens-sparing approach either had a lead contact lens shield (7 cases) or a hanging lens block (1 case) in the AP field.

Methods and Materials: Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32–89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000–4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000–5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6–232).

Results: The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival. Seven patients (15%) developed distant recurrence (brain 2, extremity 2, mediastinum 1, liver 1, and retroperitoneum 1). One patient (2%) developed cervical node metastasis. The 5- and 10-year cataract-free survival rate was 56.7% and 32.9%, respectively. Of the 12 lens complications, 8 were LENT Grade 1 and 4 were Grade 3 toxicity. Only male gender predicted for an increased risk of cataract formation. Radiotherapy dose and technique did not predict for cataract formation; however, none of the patients who underwent the lens-sparing technique developed Grade 3 lens toxicity or required surgical correction. Of the nine corneal events, two were Grade 1, four Grade 2, and three were Grade 3 toxicity. Ten dry eyes were recorded; all were mild, and no patient had severe dry eye syndrome. Neovascular glaucoma was seen in 1 patient. No injury to the retina or optic nerve was reported.

Discussion

Orbital lymphoma is a rare type of malignancy. As a result, most of the current literature consists of single-institution retrospective reviews. In this report, we present one of the largest single-institution experiences in early-stage orbital lymphoma treated with curative intent. Other studies have had a smaller number of cases and some have included more advanced or palliative cases.

Local control with RT for orbital lymphoma is excellent. Table 4 summarizes the modern literature concerning orbital lymphomas. Local control rates have ranged from 89% to 100%, with a distant metastases rate of 0–25%. Our experience showed that 15% of patients developed distant relapse, consistent with previously reported studies. The only exception was a study from the University of Florida that showed a 39% and 67% distant metastasis rate for low- and intermediate/high-grade tumors, respectively.

We did not find a statistically significant difference in relapse-free survival among low-grade and intermediate/high-grade tumors; however, the median relapse-free survival time was longer in those with low-grade tumors (13.92 vs. 7.17 years). A larger number of patients may have shown a statistical difference.

The staging workup for orbital lymphoma is controversial. What tests should be required to evaluate a patient with orbital lymphoma? Table 4 shows the different tests used at various institutions. Most of the studies had inconsistent staging tests, with the exception of two . The M. D. Anderson study used chest X-ray, CT scan of the orbit, CT scan of the chest and abdomen, and bone marrow biopsy in all 18 patients. The 5-year local control rate was 100%, with a 0% distant metastasis rate for low-grade tumors. One of 3 patients with intermediate/high-grade tumor developed a distant relapse. The Mallinckrodt study included chest X-ray and CT of the orbit and of the abdomen and pelvis in all patients and a bone marrow biopsy in all but 1 patient. The local control rate was 100%, with a 5% distant metastasis rate. Could the excellent results in the M. D. Anderson and Mallinckrodt institutes be a function of patient selection, with only the true Stage I patients analyzed? The patterns of failure in our study do not support this hypothesis. Of the eight distant and regional metastasis sites, five (brain 2, extremity 2, cervical node 1) would not have been found by CT of the chest, abdomen, or pelvis or bone marrow biopsy. The median time to relapse was 36 months (range 6–149), suggesting that most, if not all, of these relapses were not present at the initial diagnosis. Furthermore, excellent results have been reported by other studies with “incomplete” staging).

Exactly what dose should be used for low-grade and intermediate-grade tumors is not clear in the present study, because all cases were locally controlled. Follicular lymphomas and extranodal marginal zone B-cell lymphomas of the MALT type were treated with a median dose of 3000 cGy (range 2000–4020), and diffuse large B-cell lymphomas and mantle cell lymphomas had a median dose of 4000 cGy (range 3000–5100). We recommend 3000 cGy for follicular and extranodal marginal zone B-cell lymphomas of the MALT type and 3600 cGy in conventional fractionation for diffuse large B-cell and mantle cell lymphomas. It is possible that doses <3000 and 3600 cGy may be enough. Four follicular or extranodal marginal zone B-cell lymphomas received doses of 2000, 2000, 2880, and 2975 cGy, given in conventional fractionation, and were locally controlled. Nine of 19 diffuse large B-cell or mantle cell lymphomas received 3000–3960 cGy (3000 cGy in 4, 3600 cGy in 4, and 3960 cGy in 1), and 10 received doses of 4000–5100 cGy in conventional fractionation and were locally controlled.

Bolek treated 12 patients with low-grade lymphoma that were locally controlled with doses ranging from 1500 to 2600 cGy using 156–200-cGy fractions. Smitt and Donaldson  only had 1 patient with low-grade lymphoma receiving 2800 cGy; this patient subsequently developed a relapse and was salvaged by surgical excision. At the M. D. Anderson Cancer Center, 1 case of intermediate-grade lymphoma received 3600 cGy in 18 fractions without chemotherapy and was controlled; one orbit with diffuse large cell lymphoma received 3060 cGy in 17 fractions with chemotherapy and was controlled.

Most complications in our experience were mild, requiring no intervention. No cases of retinopathy, optic nerve injury, or severe dry eye syndrome were reported. Men were found to be more likely to develop cataracts after RT than were women. The RT dose, fractionation, beam energy, beam arrangement, lens-sparing technique, and use of concurrent steroids were not statistically related to cataractogenesis. Cataracts were found in 12 lenses, two-thirds of which were not symptomatic and were found only on routine follow-up. Four lenses, however, required surgical intervention. All four Grade 3 lens toxicities developed in patients who had been treated without a lens-sparing technique. Because of the higher grade of cataracts in those treated without a lens-sparing technique, we recommend a lens-sparing approach whenever feasible. The available literature is presented in Table 5 and supports this approach. Of 76 and 103 cases treated with or without lens shielding, 13% and 27%, respectively, developed a cataract (p = 0.023)

Three patients had Grade 3 corneal toxicity, all with ulceration and requiring topical antibiotics. Because the primary function of the cornea is refraction, an alteration in corneal shape such as ulceration and scar formation can cause significant refractive changes and alter vision. However, none of the three required surgical intervention. The tolerance dose of the cornea has been reported to be 5000 cGy in conventional fractionation, although some have indicated that a dose of 3000 cGy can result in keratitis if larger than conventional fractionation is used. All our patients who developed corneal ulceration received <5000 cGy with conventional fractionation.

One patient developed neovascular glaucoma. This is an uncommon RT complication caused by abnormal vascularization and subsequent closure of normal aqueous outflow channels resulting in increased intraocular pressure. Neovascular glaucoma is more commonly seen in patients treated with plaque RT). Takeda and colleagues  have previously reported a 14% incidence of neovascular glaucoma in those receiving >5000 cGy external beam RT to the iris.

The issue of bilaterality in orbital lymphoma is interesting. In our study, 5 (11%) of 47 patients had bilateral disease. At Stanford University, researchers have found a 25% incidence of bilaterality, and at University of Florida, 10% of localized orbital lymphoma developed a metachronous, contralateral orbital lymphoma at 3.8 and 5.5 years . Reddy   found a 24% incidence of bilateral disease in 17 patients. Others have not reported any bilateral cases

Conclusion: Radiotherapy alone is a highly effective modality in the curative management of primary orbital lymphoma. Most complications were minimal and did not require medical or surgical intervention. Although the use of the lens-sparing technique did not influence the incidence of cataractogenesis, we continue to recommend this approach whenever possible, because our experience indicates a higher grade of toxicity occurs and a higher incidence of corrective surgery is needed in patients treated without lens protection.