Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort

Key Points

Question  What are the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL)?

Findings  This retrospective multicenter study included 55 patients, largely elderly and male, with stage IVE OA-MCL involving bilateral tumor masses (frequently affecting the orbit). Five-year disease-specific survival was 38%, which can potentially be improved through the addition of rituximab to the chemotherapy treatment.

Meaning  Ocular adnexal MCL tends to manifest as bilateral tumor masses of the orbit, most often in men; it has an aggressive clinical course with poor prognosis.

Importance  To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort.

Objective  To characterize the clinical features of OA-MCL.

Design, Setting, and Participants  This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months.

Main Outcomes and Measures  Overall survival, disease-specific survival, and progression-free survival were the primary end points.

Results  Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region.

Conclusions and Relevance  These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.

Mantle-cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that originates in peripheral B cells of the inner mantle zone. It is characterized by chromosomal translocation t(11;14)(q13;q32), which results in upregulation of BCL-1, the gene that encodes protein cyclin D-1.^1-4 Mantle-cell lymphoma accounts for approximately 9% of all cases of non-Hodgkin lymphoma. The annual incidence of this subtype has increased during recent decades to 1 to 2 per 100 000 persons.²

Mantle-cell lymphoma is a disease of older individuals (median age, 71 years) and is more common in men than in women by a ratio of 3:1.^1,5-8 The clinical course of MCL is typically aggressive; it usually presents with widespread disease and is characterized by frequent recurrences and a poor survival rate.^1,2,8-10 In the past, management had been limited to palliative therapy, which mainly consisted of anthracycline-based chemotherapy.^11,12 During recent decades, however, novel strategies combining chemotherapy such as cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) with anti-CD20 agent rituximab (R-CHOP) have shown improved response rates and survival rates.^13,14

Mantle-cell lymphoma in the ocular adnexa represents 2% to 7% of all non-Hodgkin lymphomas.^15-19 Clinicopathological reports of ocular adnexal MCL (OA-MCL) have been published in only a few studies^9,20,21 with a limited number of cases (mean, 7), typically involving a single eye cancer center. Therefore, the aim of the present study is to evaluate the clinicopathological features of OA-MCL in a large cohort of patients from 6 eye cancer centers.

Eligible patients with a diagnosis of OA-MCL were identified from the databases of 6 eye cancer centers. The cases were collected via a review of medical records from January 1, 1980, through December 31, 2015.

For histopathological examination, the specimens were stained with hematoxylin-eosin and analyzed immunohistochemically using the following panel of antibodies known to be clinically significant in lymphoma: Bcl-2 , Bcl-6, CD3, CD5, CD10, CD20, CD23, and CD79a; cyclin D-1; and MIB-1, an antibody used to establish the presence of Ki-67, a protein associated with cellular proliferation. Because the data collection spanned 36 years and encompassed 6 international eye cancer centers, not all the samples were analyzed in this uniform manner. However, all cancer centers had subsequently reviewed the specimens independently of the study and had reclassified them according to the World Health Organization publication Classification of Tumours of Haematopoietic and Lymphoid Tissues²² and, where required, performed additional immunostaining.

The study followed the tenets of the Declaration of Helsinki and the US Health Insurance Portability and Accountability Act of 1996. Institutional review board and health information privacy agency approvals were obtained from the Danish Data Protection Agency and local ethics committees, and the study followed standard consent procedures for oral and/or written consent in each location.

The following clinical data were recorded: age and sex of the patient, symptoms, clinical findings, laterality, systemic involvement according to the Ann Arbor staging classification,²³ year of diagnosis (before or after the US Food and Drug Administration approval of rituximab in 1997), treatment approaches, response to therapy, survival duration, and cause of death.

Systemic involvement and laterality were determined using clinical information and diagnostic tools available at the time of diagnosis. Currently, a complete diagnostic procedure includes a positron emission tomography/computed tomography scan of the entire body, computed tomography or magnetic resonance imaging of the ocular adnexal region, and a bone-marrow biopsy.

Primary ocular adnexal lymphoma is defined as a biopsy-verified lymphoma in the orbit, conjunctiva, lacrimal gland, lacrimal sac, and/or eyelids, without history of systemic lymphoma. Stage IE disease is limited to the ocular adnexal region (where E indicates the involvement of the extranodal site), while stage IIE indicates involvement of unilateral preauricular or submandibular lymph nodes or adjacent structures. Stage IVE indicates involvement of 1 or more organs or tissues outside the lymphatic system. Each sample in the present study was assessed for stage, and the extent of ocular adnexal involvement of primary lymphomas was evaluated according to the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system for ocular adnexa lymphoma.²⁴

Overall survival, disease-specific survival (DSS), and progression-free survival were considered the primary end points. Overall survival was defined as the length of time from the date of diagnosis to the date of death from any cause (or to the date of last contact, a censored event). Disease-specific survival was defined as the time from the date of diagnosis to the date of death from lymphoma (or to the date of last contact, a censored event). Progression-free survival was calculated as the time from the date of diagnosis to either the date of first relapse or first sign of progression after initial treatment; in this case, the date of death from any cause and the date of last contact were both considered censored events. Kaplan-Meier plots were generated to visualize survival outcomes, and different risk groups were compared using the log-rank test. Individual risk factors were compared using the χ² test. Cox proportional hazard modeling was used to estimate each hazard ratio (HR). Statistical calculations were performed using SPSS Statistics version 22 (IBM Corporation).

A total of 55 patients with OA-MCL were identified from the databases of eye cancer centers in Copenhagen, Denmark (n = 27); Houston, Texas (n = 14); Liverpool, England (n = 10); New York, New York (n = 2); Atlanta, Georgia (n = 1); and Melbourne, Victoria, Australia (n = 1). Selected patient data from the cancer centers in Copenhagen, New York, and Houston were previously published in local studies on various histologic subtypes of ocular adnexal lymphoma.^9,19,25

Forty-two of the patients were male (76%) (Table 1). The mean age was 70 years (range, 34-90 years), and the median follow-up time was 33 months (range, 1-162 months). The patients were predominantly white (n = 37 of 41; 90%). Tumor or swelling (n = 22 of 29; 76%) and irritation (n = 15 of 29; 52%) were the most common symptoms (Figure 1). The median symptom duration was 6 months (range, 1-24 months). The most common clinical signs were a mass (n = 27 of 36; 75%) and globe displacement (n = 9 of 36; 25%). Serum lactate dehydrogenase levels were available in 19 patients, of whom 12 (63%) had elevated levels.

Eight patients (15%) were diagnosed with primary OA-MCL, 34 (62%) had systemic lymphoma with an additional manifestation in the ocular adnexa, and 13 (24%) presented with a relapse of systemic lymphoma in the ocular adnexal region. Of the 8 patients with primary lymphomas, 6 had unilateral disease (75%). Bilateral manifestation was common among patients with disseminated OA-MCL (n = 19 of 34; 56%) and relapsed disease (n = 5 of 13; 38%).

The orbit was the most frequently involved ocular adnexal site among patients with primary OA-MCL (n = 6 of 8; 75%), as well as disseminated (n = 19 of 34; 56%), and relapsed disease (n = 7 of 13; 54%) (Table 2). The conjunctiva was likewise frequently involved in 25% (n = 2 of 8), 35% (n = 12 of 34), and 23% (n = 3 of 13) of primary, disseminated, and relapsed OA-MCL, respectively.

According to the Ann Arbor staging system,²³ 7 of the 8 patients with primary OA-MCL were initially seen with stage IE disease, while patients with disseminated and relapsed OA-MCL predominantly had stage IVE disease at diagnosis (n = 26 of 34, 76%; n = 9 of 13, 69%) (Table 1).

The AJCC TNM staging was performed in the 8 patients with primary lymphomatous disease. Of these patients, 6 had stage T2 disease (involving the orbit with or without the lacrimal gland) and 2 had stage T3 disease (which involved the preseptal eyelids). The posterior orbit (T2c) was the most frequently involved site in T2 disease, followed by the anterior orbit without the lacrimal gland (T2a). Lymph node involvement (TxN1Mx, per AJCC stages) was present in 1 of the 8 patients.

Chemotherapy with or without external beam radiation therapy (EBRT) was the most frequently used treatment approach among primary, disseminated, and relapsed lymphomas (50%, 41%, and 53%, respectively) (Table 1). The median prescribed EBRT dose was 30 Gy (range, 4-50 Gy). (To convert to rad, multiply by 100.) The applied chemotherapy types included CHOP, alkylating agents, and chemotherapy unspecified in medical records. Rituximab in combination with chemotherapy (with or without EBRT) was used in the treatment of 19 of 51 patients in the study (37%), all of whom had stage IVE disease, with the exception of 1 person with disease at stage IE. Among stage IVE lymphomas, this treatment approach was applied more frequently in Houston (n = 10 of 13; 77%) compared with the remaining eye cancer centers (n = 8 of 20; 40%) (Table 3).

Median follow-up time was 33 months (range, 1-162 months). Recurrence or progression was observed in 84% of patients (32 of 38; 95% CI, 72-96) after primary treatment, and in 62% of patients (8 of 13; 95% CI, 36-88) who presented with a relapse of systemic lymphoma in the ocular adnexal region (Table 1). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) and 4.1 years (95% CI, 3.9-4.3 years), respectively. The site of relapse was accessible in 29 patients with OA-MCL, of whom 8 had recurrence within the ocular adnexal region (5 of these had involvement in the orbit), 14 had ocular adnexal recurrence in conjunction with nodal and/or extranodal involvement, and 7 had recurrence in nodal and/or extranodal sites outside the ocular adnexal region.

Survival data were available for all 55 patients. The OS rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). The 3-year and 5-year DSS rates were 72% (95% CI, 60%-84%) and 38% (95% CI, 25%-51%), respectively.

The 5-year DSS was not significantly different in patients with primary, disseminated, or relapsed lymphoma and was likewise not associated with Ann Arbor stage of disease (P = .27 and P = .42, respectively). The 5-year DSS was better among patients with disseminated lymphoma diagnosed after 1997 (57%; 95% CI, 42%-72%) than those diagnosed before 1997 (22%; 95% CI, 9%-35%) (P = .04). Since rituximab treatment became available in 1997, patients with stage IVE disease receiving rituximab in addition to chemotherapy (with or without EBRT) had a better 5-year DSS (79%; 95% CI, 65%-93%) than patients who were not treated with rituximab (25%; 95% CI, 11%-39%) (P = .04) (Figure 2). The 5-year DSS was better among patients with disseminated lymphoma from Houston (100%) than from Liverpool (0%; P = .01) and was more favorable for patients with stage IVE disease from Houston (100%) than patients with stage IVE disease from Copenhagen (28%; P = .005) (Table 3). After adjusting for eye cancer center, patients receiving rituximab in addition to chemotherapy (with or without EBRT) had a better disease-specific survival at 5 years than patients who did not receive rituximab (HR, 3.3; 95% CI, 1.0-14.7; P = .06).

Ocular adnexal MCL was found to present primarily in older male individuals, and it appeared to be an aggressive malignant condition with a frequent occurrence of dissemination (62%; 95% CI, 49%-75%), bilateral ocular adnexal manifestation (47%; 95% CI, 34%-60%), and a poor prognosis (5-year DSS, 38%; 95% CI, 24%-50%), which could potentially be improved by addition of rituximab to the chemotherapy regimen.

The predominance of OA-MCL among older male individuals, as detected in this study, is consistent with the results of previous research.^1,5-8 The sex difference associated with this disease is among the most pronounced in lymphoma, with a similar male predominance found only in hairy-cell leukemia (which has a male–female ratio of 3.3:1) and Burkitt lymphoma (with a male–female ratio of 3.1:1).²⁶ Genetic studies propose that this striking sex difference might be explained by an age-related effect in older cells that increases the risk of loss of sections of the Y chromosome, in combination with the suppression of a tumor suppressor gene on the X chromosome.²⁷

The high proportion of disseminated lymphoma identified in the present study is likewise in accordance with previous studies of MCL.^1,2,8,9 The tendency for lymphoma to disseminate throughout the body is probably related to the derivation of MCL from pregerminal center B lymphocytes, which express specific adhesion molecules and chemokine receptors that allow them to circulate continuously to secondary lymphoid tissues.²⁸ This predisposition toward widespread disease likely explains the high proportion of bilateral disease identified among OA-MCLs in this study.

Current lymphoma treatment guidelines recommend R-CHOP or similar chemotherapy for management of MCL at all stages.² This approach was only used to treat 19 patients in the present study, which might be because the study spanned a 36-year period, and rituximab has only been available since 1997.²⁹

The presented data confirm that MCL has a poor prognosis.^{1,15,16,30-32} As other studies have shown, survival can potentially be improved by the addition of rituximab to chemotherapy treatment.^13,14 The fact that patients from Houston had a better outcome than patients from Liverpool and Copenhagen may be explained in part by the higher proportion of patients from Houston who were diagnosed after 1997 and who consequently received rituximab in combination with chemotherapy. Studying patients with primary OA-MCL across relatively similar lengths of the follow-up period established that all had recurrences after treatment except 1 patient, who had received rituximab-containing chemotherapy. Therefore, the present findings highlight the importance of adding rituximab to the chemotherapy treatment, including in patients whose OA-MCL is localized.

The retrospective design of this multicenter study poses some inherent limitations. The data were pooled across 6 oncology centers over a 36-year period, which entailed incomplete medical records and varying diagnostic and treatment methods, which made evaluation of treatment approaches particularly challenging. As the present study deals with a rare subtype of lymphoma in the ocular adnexa, the number of patients is low. This makes it less certain that these findings are truly representative. Furthermore, the median follow-up was 33 months, which might not have been enough time to detect the outcome variables in some cases. On the other hand, multicenter studies like this, obtaining a reasonable number of patients, provide valuable information on relatively rare lesions such as OA-MCL.

The results of this study confirm that OA-MCL manifests most commonly in older men. The clinical course of this disease appears to be aggressive, with patients frequently presenting with disseminated lymphoma at stage IVE, with bilateral tumor masses that frequently involve the orbit. Treatment commonly requires chemotherapy, with or without EBRT. These data suggest that the prognosis for these patients is poor; however, the findings suggest that survival can potentially be improved by addition of rituximab to the chemotherapy regimen. Further research is necessary to identify more clinical features associated with earlier detection of MCL in patients with OA-MCL to potentially improve their prognosis.

Corresponding Author: Steffen Heegaard, MD, DMSc, Department of Pathology, Rigshospitalet, University of Copenhagen, Frederik V’s Vej 11, First Floor, DK-2100 Copenhagen, Denmark (sthe@sund.ku.dk).

Accepted for Publication: September 23, 2017.

Published Online: November 9, 2017. doi:10.1001/jamaophthalmol.2017.4810

Author Contributions: Dr Knudsen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Knudsen, Heegaard, Rasmussen, Coupland, Ralfkiaer.

Acquisition, analysis, or interpretation of data: Knudsen, Heegaard, Coupland, Esmaeli, Finger, Graue, Grossniklaus, Khong, McKelvie, Mulay, Sjo, Vemuganti, Thuro, Curtin.

Drafting of the manuscript: Knudsen, Heegaard, Coupland, Esmaeli, Graue.

Critical revision of the manuscript for important intellectual content: Heegaard, Rasmussen, Esmaeli, Finger, Grossniklaus, Khong, McKelvie, Mulay, Ralfkiaer, Sjo, Vemuganti, Thuro, Curtin.

Statistical analysis: Knudsen, Heegaard.

Obtained funding: Knudsen, Heegaard, Finger.

Administrative, technical, or material support: Heegaard, Grossniklaus, Khong, McKelvie, Mulay, Sjo, Vemuganti, Thuro.

Study supervision: Heegaard, Rasmussen, Coupland, Esmaeli, Finger, Graue, Ralfkiaer.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported.

Funding/Support: This work was supported by grants from Fight for Sight Denmark, the Danish Cancer Society, the Danish Eye Research Foundation, Synoptik Foundation, the Danish Foundation for Cancer Research, Engineer Lars Andersens Foundation, the A. P. Møller Foundation for the Advancement of Medical Science, the Merchant Kjaer and Wife Kjaer, born la Cour-Holmens Foundation, and The Eye Cancer Foundation.

Role of the Funder/Sponsor: The funding sources and organizations had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.