After a distinctive type of lymphoma arising from mucosa-associated lymphoid tissue (MALT) had been recognized by Issacson and Wright, it has been found that MALT lymphoma is the most common histologic subtype of orbital lymphoma. MALT lymphomas are generally indolent, and usually respond well to local radiotherapy (RT). However, literature information concerning the etiology and clinical behavior of orbital MALT lymphoma is limited and inconsistent.

Before the introduction of immunophenotypic analysis, it was not easy to differentiate a low-grade lymphoma from a reactive lymphoid infiltrate. Therefore, the literature on lymphoproliferative disease of the orbit varies histopathologically, reporting from benign to malignant to indeterminate histologies. The clinical behavior and treatment outcome from different institutions were difficult to interpret and compare. Recently, several reports have focused specifically on the natural history of this disease. Orbital MALT lymphoma revealed a higher rate of distant relapse than nonorbital MALT lymphoma, thus a thorough staging workup study was suggested. However, most reports had various limitations in interpreting the results such as incomplete staging workup, inclusion of different histologic subtypes, and short follow-up periods.

In Korea, the incidence of MALT lymphoma is relatively high, and extranodal lymphomas are more common than nodal lymphomas. The incidence of orbital lymphoma has increased in the last decade, comprising 3.9% of non-Hodgkin’s lymphoma according to a 1998 report. We have encountered a significantly large number of patients with low-grade orbital lymphoma in a short period of time at a single institution. We performed extensive staging workup on patients with biopsy-proven low-grade orbital lymphoma, treated them with RT alone, and then performed follow-up analysis.

The aim of the current study was to elucidate the clinical behavior and treatment outcomes of low-grade primary orbital MALT lymphoma by thorough staging workup and long-term follow-up after RT.

Treatment

All patients except 1 were treated with radiotherapy alone. Lesions confined to the conjunctiva or eyelids were treated with a single anterior direct field using a 6–9 MeV electron beam. The entire bulbar and palpebral conjunctiva was treated. The cornea and lens were shielded with a custom-made contact lens if the lymphoma did not encroach toward the limbal structures. The contact lens was made of resin and bore a lead with a diameter of 10 mm and a thickness of 2 mm inside. Retrobulbar tumors were irradiated with multiple photon beams (Co-60 or 4-MV X-ray). The clinical target volume was the entire orbital cavity. Field arrangement was usually a combination of anterior and wedged, both lateral 3-fields, or a wedge pair technique consisting of an anterior field and an ipsilateral anterior oblique field. A hanging eye bar block was used in the anterior field to shield the cornea and lens. After experiencing recurrent retrobulbar tumors at the shielded area, we did not use the hanging eye bar block if retrobulbar tumor was present in the shielded area. All of the patients were immobilized with a thermoplastic mask during treatment. Radiation dose ranged from 5.4 to 30.6 Gy with a median dose of 30.6 Gy, with a fraction size of 1.8–2.0 Gy. Only 2 patients received less than 25.2 Gy of radiation, with 1 patient receiving 5.4 Gy and the other receiving 21.6 Gy. Complete response (CR) was defined as the complete disappearance of all clinical evidence of lymphoma by physical examination and orbital CT scan. Follow-up periods were between 13 and 144 months (median, 70 months). Forty patients (83.3%) were followed for more than 5 years or until death.

Methods and Materials: Forty-eight patients with pathologically confirmed marginal zone B-cell lymphoma of MALT were treated with radiotherapy (RT). Thirty-eight patients (79.1%) received thorough staging workup studies including bone marrow biopsy. Radiation doses ranged from 5.4 to 30.6 Gy (median, 30.6 Gy). Median follow-up period was 70 months.

Results: Only 2 patients revealed extraorbital lymphoma involvement (bone marrow, skin). Forty-six of 52 eye lesions showed complete response to RT. Six lesions demonstrated a partial response and showed gradual regression during the follow-up period of 39–72 months. Three patients experienced local recurrences at 34, 48, and 52 months after RT, which seemed to be related to improper use of the lens shield. Salvage re-RT was successful. The 10-year actuarial relapse-free survival, cause-specific survival, and overall survival rates were 93.1%, 97.9%, and 86.9%, respectively.

Complications

Acute reaction from radiotherapy was minimal in all patients. A mild degree of periorbital soft tissue swelling, which subsided gradually in a couple of months, was noted in most patients. Some patients revealed a mild degree of acute conjunctivitis, which was treated successfully with artificial tears. Two patients developed cataracts, 39 and 56 months after RT, which were successfully corrected with operation. None of the patients experienced keratitis or retinopathy, or required ongoing occasional use of artificial tears.

There was no systemic relapse during the follow-up period. Only one contralateral orbital relapse was noted 89 months after RT in a patient who also had ipsilateral local recurrence. Reports from Japan also stated a lower rate of distant relapse. In contrast, a distant relapse rate of 15–23% for low-grade primary orbital lymphoma was reported in Western countries. A more recent study by Fung . also reported a high distant relapse rate for Stage I ocular adnexal MALT lymphoma. The distant relapse–free survival rate was 75% at 5 years and 45% at 10 years . A longer follow-up period and a greater number of patients from different countries are needed to determine whether there is a geographic difference in the rate of distant relapse.

Our observations suggest that most MALT lymphomas of the orbit are a localized disease and have a very favorable prognosis. Because the incidence of extraorbital involvement at diagnosis was very rare and disease progression is slow, allowing the patient to be treated successfully at the time of a symptomatic relapse, extensive workup studies at diagnosis may not be needed. Furthermore, even in cases with systemic low-grade lymphoma, chemotherapy is usually not effective and cannot cure the disease. Therefore, early diagnosis and treatment of an asymptomatic lesion cannot alter the clinical course. It is well known that MALT lymphomas relapse at other MALT sites such as skin or subcutis, breast, parotid gland, and thyroid gland, which can be detected with physical examination. Recently after this study period, we experienced two cases of orbital MALT lymphomas that had extraorbital manifestations, one at the skin and one at the abdominal subcutaneous tissue. No patient revealed internal organ involvements during the follow-up period. Only 1 patient with bone marrow involvement at diagnosis died of lymphoma. He had multiple cervical lymphadenopathy besides bilateral ocular involvement at the initial presentation. Therefore, we would conclude that extensive staging workup study at diagnosis and periodic follow-up study is not crucial in the management of low-grade orbital lymphoma.

It has been reported that anatomic subsites of disease have prognostic significance. Conjunctival lesions less frequently relapsed systemically than orbital or eyelid lesions. It was interpreted that this was due to the fact that most conjunctival lesions were low-grade. Suzuki et al. suggested that conjunctival lymphoid infiltrates usually have the features of MALT lymphoma with genotypic B lymphocytic monoclonality. Others, however, have observed no correlation between disease subsite and systemic relapse. In the current study, there was no predilection site for MALT lymphoma and all showed excellent outcomes. No increased frequency of conjunctival or lachrymal gland involvement by MALT lymphoma was found in another study

Because it is well known that an excellent control rate can be achieved with 20–35 Gy of radiation in low-grade orbital lymphoma, and because there were no serious late toxicities at a dose of less than 30 Gy, we prescribed 25.2–30.6 Gy with 1.8–2.0 Gy per fraction. One patient, with bilateral conjunctival masses, received only 5.4 Gy in 3 fractions but tumors disappeared in a few weeks and CR was maintained until death resulting from systemic lymphoma 50 months after RT. Other series also reported excellent local control with 15–20 Gy. Because the risk of RT-related complications should be minimized, it is important to reduce the radiation dose if possible. At present, we are prescribing 25.2 Gy for orbital MALT lymphoma treatment.

Lens shielding was applied in most cases, which resulted in a very low rate of late complication. However, three local recurrences seem to be related to the lens shielding technique. One conjunctival mass was very extensive, nearly encroaching on the cornea. A dose of 26 Gy of 6-MeV electron beam and a custom-made lead contact lens device to shield the cornea and lens were used to treat this patient. The contact lens might cause overshielding of the conjunctiva around the cornea. In the other 2 patients with local recurrence, the recurrent tumor sites were exactly compatible with the inadequate dose area corresponding to the hanging bar block. Because cataracts can be easily corrected with operation and a major complication, such as corneal ulceration, is rarely observed with radiation less than 30 Gy, an optimal lens shielding that does not compromise tumor control is recommended. Currently, we do not use a hanging eye bar block if the tumor is shielded.

Because clinical behavior is indolent and almost all cases can be controlled with low-dose radiation regardless of tumor bulk, the optimal time to administer radiation should be considered. No debate is needed when administering radiation to treat a newly diagnosed orbital lymphoma because of the obvious signs and symptoms. However, it is very difficult to decide whether or not to administer radiation for an asymptomatic orbital relapse after CR or newly developed contralateral lesion. We are closely following the patients with minimal contralateral conjunctival lesions without progression. Also we have followed 6 partial response cases without boost RT. All lesions showed gradual regression. Our current policy is to administer RT when symptoms develop or progression is noted.

In conclusion, most of the MALT lymphomas of the orbit were localized at diagnosis and extraorbital relapse rarely occurred. Therefore, extensive staging workup at the time of diagnosis and follow-up studies to detect distant relapse may not be obligatory. We suggest that orbit CT scan, careful physical examination, complete blood count with differential count, liver function test, and chest X-ray are sufficient for a systemic evaluation of orbital MALT lymphoma. Further studies such as CT scans of the chest, abdomen, and pelvis, gallium scan, and bone marrow biopsy are recommended only for patients with positive findings on initial workup studies. Carefully planned low-dose RT alone with proper lens shield that does not compromise tumor control is the optimal treatment modality for orbital MALT lymphomas.
Conclusion: Most of the MALT lymphoma of the orbit was localized at diagnosis and extraorbital relapse rarely occurred. Therefore, extensive staging workup at the time of diagnosis and follow-up studies to detect distant relapse may not be obligatory. Low-dose RT alone with proper lens shielding is the optimum treatment modality for orbital MALT lymphoma.