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Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa Jean Guffey Johnson, MD, Lauren A

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Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa Jean Guffey Johnson, MD, Lauren A Evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics as initial treatment for localized extranodal marginal zone B-cell lymphoma of the ocular adnexa. Photo courtesy of Lynn E. Harman, MD. Los Angeles. Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa Jean Guffey Johnson, MD, Lauren A. Terpak, MS, Curtis E. Margo, MD, and Reza Setoodeh, MD Background: Low-grade B-cell lymphomas located around the eye present unique challenges in diagnosis and treatment. Extranodal marginal zone B-cell lymphoma is the most common lymphoma of the ocular adnexa (conjunctiva, orbit, lacrimal gland, and eyelid). Methods: A systematic search of the relevant literature was performed. Material pertinent to the diagnosis, prognosis, pathogenesis, and treatment of extranodal marginal zone B-cell lymphoma of the ocular adnexa was identified, reviewed, and analyzed, focusing on management strategies for primary localized disease. Results: The primary cause of extranodal marginal zone B-cell lymphoma of the ocular adnexa remains elusive, although an infectious agent is suspected. Radiotherapy is the most common initial treatment for lo- calized disease. Initial treatment with chemotherapy, immunotherapy, and antibiotics has shown promising results, but the number of series is limited and controlled trials do not exist. Conclusions: Although the long-term outcome of localized extranodal marginal zone B-cell lymphoma of the ocular adnexa is good, optimal treatment remains a goal. The variation in rates of local and systemic re- lapse among treated stage 1E tumors suggests that critical factors affecting outcomes are not fully understood. Radiotherapy is the standard of care; at this time, the evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics for initial treatment of extranodal marginal zone B-cell lymphoma localized to the ocular adnexa. Well-controlled comparative studies are needed. Introduction orbit and lacrimal gland, ranking third behind squa- Lymphomas are the most common malignancy of the mous cell carcinoma and melanoma among the ma- lignancies of the conjunctiva.1-3 The eyelid is an un- common site of primary lymphoma and is more often From the Department of Pathology (JGJ, RS), James Haley Veterans Hospital, Departments of Ophthalmology and Pathology and Cell secondarily involved when tumors spread from the Biology (CEM), Morsani College of Medicine (LAT), University of conjunctiva or orbit.4,5 The incidence of ocular adnexal South Florida, Tampa, Florida. lymphoma has increased in recent decades, primarily Address correspondence to Curtis E. Margo, MD, Department of due to an increase in extranodal marginal zone B-cell Ophthalmology, MDC Box 21, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612. E-mail: [email protected] lymphoma of the mucosal-associated lymphoid tissue 1,4,6,7 Submitted July 27, 2015; accepted October 5, 2015. (MALT) type. Most types of lymphoma have been No significant relationships exist between the authors and the reported in periocular tissues, of which 95% or more companies/organizations whose products or services may be ref- are B cell in origin; extranodal marginal zone B-cell erenced in this article. lymphoma is the most frequent, making up approxi- The authors discuss unlabeled/unapproved uses of doxycycline and clarithromycin for extranodal marginal zone B-cell lympho- mately 70% of cases, followed by follicular lymphoma ma of the ocular adnexa. and diffuse large B-cell lymphoma.5,8-15 Extranodal 140 Cancer Control April 2016, Vol. 23, No. 2 marginal zone B-cell lymphoma of the ocular adnexa tered. These larger cells are usually positive for B-cell shares similar features with extranodal marginal zone chronic lymphocytic leukemia/lymphoma (BCL) 6 and B-cell lymphoma located elsewhere, including general sometimes cluster designation (CD) 10.17 morphology and immunophenotype, and, presump- Given the morphological overlap between reactive tively, pathogenesis. Extranodal marginal zone B-cell lymphoid hyperplasia and extranodal marginal zone lymphoma of the ocular adnexa is a presumed antigen- B-cell lymphoma, ancillary tests are often used to en- driven neoplasm based on the model of gastric extra- hance diagnostic certainty. Extranodal marginal zone nodal marginal zone B-cell lymphoma. The putative B-cell lymphomas are positive for CD20, BCL2, paired antigenic stimulus (or stimuli) is a subject of investiga- box 5 (PAX5), and CD79A but typically do not express tion. CD5, CD10, or CD23.16 Fewer than 5% of cases express We provide a general overview of extranodal mar- CD5.11-14,16 In the setting of CD5 positivity, the differ- ginal zone B-cell lymphoma of the ocular adnexa, em- ential diagnosis might include mantle cell lymphoma phasizing key similarities and differences in biologi- (positive for cyclin D1, t[11;14] present) and small lym- cal behavior and management with other MALT-type phocytic lymphoma (positive for CD23).14 CD43 ex- lymphomas in different locations. Because most cases pression is less common in extranodal marginal zone of extranodal marginal zone B-cell lymphoma of the B-cell lymphoma of the ocular adnexa compared with ocular adnexa present as localized disease, this subset the salivary glands (12%–25% vs 70%).11,18 Lymphoma of patients with lymphoma will be the focus of clinical cells typically express immunoglobulin (Ig) M and are management in this article. Therapeutic studies were IgD negative; on average, the proliferation index is 15% included if the researchers examined single treatment by Ki-67 immunostaining.19 protocols for localized extranodal marginal zone B-cell The immunohistochemical demonstration of lymphoma of the ocular adnexa (Ann Arbor stage 1E). light-chain restriction using formalin-fixed, paraffin- To avoid omitting studies containing valuable clinical embedded tissue is challenging because detection of information on the treatment of localized extranodal cytoplasmic light chains in nonplasmacytic prolifera- marginal zone B-cell lymphoma, inclusion criteria al- tions is prone to false-negative testing.20-22 An alterna- lowed series with up to 15% of cases with disease lo- tive approach to demonstrating light-chain restriction cated at other sites as long as outcomes were not col- is flow cytometry, which requires fresh tissue.23,24 Flow lectively reported. cytometry may also be useful in confirming immuno- phenotype, particularly when the size of a specimen is Diagnosis limited.23,24 Recurrent structural genetic abnormalities The histological features of extranodal marginal zone have been identified in MALT-type lymphomas, and the B-cell lymphoma are similar to those of MALT-type lym- frequency of these alterations vary, depending on ana- phomas in general. Neoplastic lymphocytes consist of tomical site.25 Although it is not specific, trisomy of chro- varying combinations of small cells resembling centro- mosome 3 is the most commonly reported cytogenetic cytes, plasmacytoid lymphocytes, and monocytoid B finding among MALT-type lymphomas.25 Among the cells, with fewer numbers of scattered large cells resem- common sites of MALT lymphomas, t(14;18)(q32;q21) in- bling centroblasts or immunoblasts. This heterogeneous volving IgH and MALT1 is the most frequently seen in population of cells is usually found among reactive fol- the ocular adnexal MALTomas.26 This translocation has licles, some of which may eventually be overrun by lym- been reported in about 25% of cases in some series.26 phoma cells (follicular colonization). Plasma cells are Clonality of B cells can be documented by polymerase prominent in some cases, and intranuclear pseudoin- chain reaction (PCR) of Ig heavy chain.27,28 clusions (Dutcher bodies) are sometimes noted. Charac- More centers are employing combinations of im- teristic infiltration of the epithelium by neoplastic lym- munohistochemistry, flow cytometry, and PCR to di- phocytes (lymphoepithelial lesion) is uncommon, and, agnosis low-grade lymphoma and relying less on mor- when observed, it is found in the lacrimal gland and phology alone.29 conjunctiva but not the orbit.16 However, collections of atypical lymphocytes in conjunctival epithelium and lac- Clinical Staging rimal ducts similar to lymphoepithelial lesions are not The approach to staging ocular adnexal lymphoma is specific for extranodal marginal zone B-cell lymphoma. similar to that for lymphoma in general, and typically They have also been described in reactive processes of includes thorough clinical and laboratory examina- the conjunctiva and lacrimal gland.16 Monocytoid cells tions with bone marrow biopsy.30 Although comput- with abundant pale cytoplasm are observed less often in ed tomography (CT) or magnetic resonance imaging extranodal marginal zone B-cell lymphoma of the ocu- (MRI) with contrast is valuable to determining the ex- lar adnexa than other sites.11 Transformation to diffuse tent of local disease of the orbit, eyelid, and paranasal large B-cell lymphoma should be considered when sol- sinuses, positron emission tomography (PET) may be id or sheet-like proliferations of large cells are encoun- superior for the initial staging of ocular adnexal lym- April 2016, Vol. 23, No. 2 Cancer Control 141 phoma.31 When compared with CT, use of PET has upstaged a majority of patients Table 1. — TNM Staging for Lymphoma of the Ocular Adnexa with ocular adnexal lymphoma.32,33 Clinical Primary Tumor Pathological Evidence suggests that subclinical in- Stage Stage volvement of the eye can occur in persons TX Lymphoma
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