Ocular adnexal lymphoma – a retrospective study and review of the literature

Lymphomas are a heterogeneous group of malignant lymphoid tumors that arise from the clonal proliferation of either B-lymphocytes, T-lymphocytes or, less commonly, of natural killer (NK) cells at different stages of maturation.^1,2 Lymphomas are divided into 2 major categories, namely Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The molecular mechanisms include several structural chromosomal abnormalities, for example translocation 14;18 in marginal zone lymphomas, translocation 11;14 in mantle cell lymphomas or bcl-2, bcl-6 and myc translocation in case of aggressive B-cell lymphomas.^1,2,3,4,5 Ocular adnexal lymphoma (OAL) is defined as lymphoma that occurs in the conjunctiva, lacrimal apparatus, eyelid, or orbit.^3,4,5,6 It represents 6−8% of orbital and 10−15% of adnexal tumors.⁷ OAL is considered primarily if it involves the ocular adnexa alone and secondarily if it is accompanied by a lymphoma of the identical type at another extraocular site.⁶ These tumors may spread locally or disseminate systemically.⁸ OAL may present with symptoms of conjunctival salmon patches, ptosis from levator muscle involvement or the insidious and painless development of proptosis with or without diplopia due to an orbital mass.⁹ In the orbit, OAL can involve the lacrimal gland, extraocular muscles, or intraconal and extraconal spaces.⁹

Diagnosis based only on clinical and imaging data is inadequate. Consequently, an incisional or excisional biopsy followed by histopathologic, immunophenotypic and molecular genetic studies, either to confirm or to rule out this malignancy, should be performed.¹⁰ Orbital imaging typically shows a poorly defined mass that molds to the shape of surrounding structures without direct invasion or bony erosion.^11,12 In addition to orbital imaging and subsequent biopsy, positron emission tomography alone or combined with computed tomography is often performed for systemic staging of disease and for the assessment of response to therapy.¹³ It is important to perform a complete systemic evaluation, both at diagnosis and at regular follow-ups, since more than half of patients will present with systemic lymphoma at the time of ocular diagnosis or will develop a systemic disease later on.¹⁴

Several successful treatment modalities for OAL have been reported so far, including surgical excision, cryotherapy, external beam radiotherapy for tumors localized to the periocular area or in combination with chemotherapy, immune modulating therapy, or primary antibiotic treatment in case of systemic involvement.¹⁵ Spontaneous remissions of the OAL have been reported in low grade lymphomas but never in high grade subtypes. In general, the outcome of OAL is favourable, however small patient numbers, patient selection criteria, varied histologic subtypes, and the lack of large prospective studies usually make the comparison of the effectiveness of different types of treatment challenging.¹⁶

The purpose of our study was to review the characteristics of all Slovenian patients with OAL in the period of 24 years with the aim of evaluating demographic data, lymphoma location and type, disease stage, treatment modality, local control rate and survival rate.

In our retrospective study we present the characteristics of Slovenian patients with OAL. The study included 74 patients with biopsy-proven OAL between 1995 and 2019 at Eye Hospital, University Medical Centre Ljubljana, Slovenia, and treated at the Institute of Oncology Ljubljana, Slovenia. Compared to median age of OAL presentation of around 60 years reported in previous studies and reviews, we registered a higher median age (68 years) in our group.^{16,21,22,23,24,25} In concordance with the previous review where female predominance of 55% was reported, we also registered a higher morbidity in women (59.5%) in our study.²⁵

Anatomically, our OAL cases were distributed inside the orbit in 56 cases (75.7%) compared to 18 cases (24.3%) located in conjunctiva. The distribution was similar to the study of Fernandez et al. where the orbital fibroadipose tissue was involved in 64% of cases and conjunctiva in 32% of cases.²² We anatomically divided OAL in the conjunctival lymphoma with characteristic salmon-pink nodular patch and in the orbital lymphoma with a presentation of mass lesion in eyelids, lacrimal gland, lacrimal sac, extraocular muscle, intraconal or extraconal space. In some studies, the eyelids were used as a separate location^16,22 but we included the eyelids’ involvement with orbital lymphoma as all our patients with involved eyelids also had an orbital progression of lymphoma. Bilateral involvement of OAL is usually seen in 7%−24% of patients¹⁶, in our series it was in 14.9%. Bilateral involvement was, however, more common in orbital lymphoma (17.9%, 10/56) than in conjunctival lymphoma (5.6%, 1/18). Of note, bilateral OAL was detected only in MALT (4/53, 7.5%), MCL (5/9, 55.6%) and FL (2/6, 33.3%) lymphoma subtypes. According to our results, although the study included a relatively small number of MCL cases, we observed that MCL was more commonly confirmed bilaterally compared to the other types of lymphoma. The study of Rasmussen et al. on ocular adnexal MCL showed also a more common bilateral disease. Furthermore, they also reported a more frequent bilateral occurrence of primary than of secondary ocular adnexal MCL.²⁶ On contrary, all our MCL patients had a secondary lymphoma or a recurrence of systemic lymphoma.

The majority of lymphomas in our study were of B-cell origin (98.6%, 73/74) similarly to the other studies where between 95% and 100% of reported cases corresponded to the B-cell type.¹⁶ Subtypes were MALT (71.6%), which is in agreement with previous studies reporting a 58% occurrence of this type²⁷, MCL (12.1%), FL (8.1%), DLBCL (5.4%), CLL (1.4%) and peripheral T-cell lymphoma, not otherwise specified (1.4%). All subtypes were found in the orbit, with the most frequent being MALT (64.23%, 35/56) and MCL (16.1%, 9/56), while only MALT (94.4%, 17/18) and FL (5.6%, 1/18) were identified in conjunctiva. Comparably, conjunctival sites were observed in literature in one third of patients and almost always consisted of low-grade NHL (96% of patients).²⁸ MCL was the only histological subtype which predominated in male patients, which is also consistent with previous studies^8,29,30,31, all other histological subtypes were predominant in female patients. The only entity that stands out in our study is a relatively high proportion of MCL, 12.2%, since this type is usually diagnosed in only 3−4% of the patients.^22,24 However, all cases of MCL in our series were located in the orbit and represented a primary or secondary manifestation of a systemic lymphoma. Further studies on larger number of patients will be needed to prove this observation.

Half of the treated patients were cured with radiotherapy or, to a minor extent, systemic treatment. Treatment guidelines suggest radiotherapy as the preferred option for localized disease in case of low-grade lymphoma.^17,19 Radiotherapy is a non-invasive treatment with known side effects, the most frequently reported cataract (12.1%) and dry eye (8.5%)²⁵, that are manageable through time. For example, cataract can be treated with surgery and the more common dry eye disease with artificial tears. The suggested radiotherapy doses range from 24 Gy up to 30 Gy.¹⁷ More than half of our patients were treated with 30 Gy, since the conclusions of a phase III trial of safely lowering the dosage to 24 Gy for indolent lymphoma was released in 201132 and our observation and treatment period of included patients began long before that.

Local control rate of 96.6% in our study is in line with Yen’s analyses (95.9% for studies of MALT lymphomas and 93.1% for studies that included data on multiple subtypes of lymphoma).²⁵ Of note, our study included both multiple histologic subtypes of lymphoma and all OAL locations. Five-year overall survival rate in our study was 80.1% similar to Yen’s pooled analyses (78.9%).²⁵ Half of our patients died due to causes unrelated to lymphoma, they were also significantly older than the rest of the study group, which underlines the importance of choosing the proper treatment or even active surveillance strategy with regard to patient’s preferences and comorbidities. The higher lymphoma-specific survival compared to the overall survival in our study shows that these patients are elderly, having other comorbidities that are more commonly the cause of death than lymphoma itself. Furthermore, we observed also a relatively high proportion of spontaneous remissions locally (54.5%, 6/11) in the active surveillance strategy group, suggesting that not all patients necessarily need the treatment immediately at presentation.

There is also an option of treating with only 4 Gy in 2 fractions for localized disease as reported by de Castro et al.³³ Park et al.³⁴ started a prospective phase II trial of 4 Gy in 2 fractions in stage I patients. Complete remission was observed in 11 lesions and partial remission in 6 of the 17 included lesions, respectively. The lesions with partial response were further treated to 24 Gy. Therefore, the future perspective for localized lesions is to reduce and adapt the radiation treatment if possible while still preserving excellent remissions and reducing the side effects.³⁴

In Tanimoto’s study with a similar follow up time as in our study³⁵, 69% of patients with MALT lymphoma did not need any treatment for localized disease. Similar to Tanimoto’s study, our active surveillance strategy group was comprised of predominately MALT histology. Even though the active surveillance group was not older than the treated group, we feel obliged to stress the importance of a careful evaluation of treatment strategy, comorbidities and patient’s preferences to avoid unnecessary additional complications caused by treatment.

Aggressive lymphomas (DLBCL, MCL, peripheral T-cell lymphoma, not otherwise specified) were treated according to guidelines with systemic treatment resulting in outcomes that are in line with reported histological subtypes.^36,37 Considering the fact that low grade lymphomas are usually incurable and the recurrence of the disease is expected, we need to underline that there were only two cases of recurrence in periocular area, that have been already treated previously. Our 5-year overall survival rate and lymphoma-specific survival rate are high (80.1%; 87.2%), but again, as reported, OALs are known for high survival rates.^16,24,38

Patients with localized disease (eye only) were in our study analyzed separately. In this group of patients, a higher 5-year overall (91.1% compared to 80.1%) and lymphoma-specific survival rate (100% compared to 87.2%), as well as a higher number of complete remissions (70.3% compared to 56.9%) and a lower number of systemic recurrences (24.3% compared to 43.1%) were registered. It can be therefore concluded that patients with a localized disease have a better outcome compared to patients with secondary OAL.

Ocular adnexal lymphomas comprise a group of heterogeneous diseases. Their outcomes vary in relation to patient’s age and lymphoma type. Individual treatment decisions are mandatory to tailor the treatment suitable for each patient. Radiotherapy has proven to be a highly efficient treatment with an excellent local control rate while systemic treatment should be reserved for disseminated disease.