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

Evidence is insufficient to recommend

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 localized 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 relapse 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 uncommon 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 immunophenotype, 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 extent not specified TX 34,35 with periocular lymphoma. In a study T0 No evidence of lymphoma T0 of ocular adnexal lymphomas, 25 study T1 Lymphoma involving the conjunctiva alone without T1 patients with bilateral involvement had orbital involvement uveal thickening with ocular B-scan ultra- T1a Bulbar conjunctiva only T1a 34 sonography. (Intraocular disease might T1b Palpebral conjunctiva ± fornix ± caruncle T1b have been missed if staging were based 34 T1c Extensive conjunctival involvement, both bulbar and T1c on CT alone. ) Although uveal involve- nonbulbar ment with extranodal marginal zone B-cell T2 Lymphoma with orbital involvement ± any conjunc- T2 lymphoma has been previously reported, tival involvement few studies have documented how often it T2a Anterior orbital involvement (± conjunctival involve- T2a goes unrecognized when patients present ment) but no lacrimal gland involvement 34,35 with conjunctival and orbital disease. T2b Anterior orbital involvement (± conjunctival involve- T2b How uveal involvement might affect prog- ment) plus lacrimal involvement nosis is also unclear. T2c Posterior orbital involvement (± conjunctival T2c Roughly two-thirds of ocular adnexal involvement ± anterior orbit involvement and ± any lymphomas are stage 1E (localized extra- extraocular muscle involvement) nodal tumors) using the Ann Arbor sys- T2d Nasolacrimal drainage system involvement T2d 8,36,37 (± conjunctival involvement but not including tem. This disproportionate accumu- nasopharynx) lation of cases in a single stage limits the T3 Lymphoma with preseptal eyelid involvement ± T3 discriminatory potential to forecast out- orbital involvement ± any conjunctival involvement comes. Other shortcomings exist to the Ann T4 Orbital adnexal lymphoma extending beyond orbit to T4 Arbor system for ocular adnexal lymphoma, adjacent structures such as bone and brain including the inability to take into account T4a Involvement of nasopharynx T4a multicentric and bilateral tumors, extent of T4b Osseous involvement (including periosteum) T4b localized tissue involvement, and precise an- 38 T4c Involvement of maxillofacial, ethmoidal, and/or T4c atomical location around the eye. frontal sinuses Application of the tumor, node, metas- T4d Intracranial spread T4d tasis (TNM)–based system incorporating information on extent of disease within Regional Lymph Nodes anatomical compartments of the ocular ad- NX Regional lymph nodes cannot be assessed NX nexa, bilateral nature, and information on N0 No evidence of lymph node involvement N0 regional lymph-node involvement may bet- N1 Involvement of ipsilateral regional lymph nodes N1 ter predict outcome (Table 1).39-42 An initial (preauricular, parotid, submandibular, and cervical) study showed that tumor stage may more N2 Involvement of contralateral or bilateral regional N2 thoroughly describe the extent of disease, lymph nodes although it does not yet predict rate of re- N3 Involvement of peripheral lymph nodes not draining; N3 ocular adnexal regional lapse or survival.41 Stages N1 to N4 and M1 are associated with worse rates of surviv- N4 Involvement of central lymph nodes N4 al.41 In a multicenter study using the TNM Distant Metastasis system, any prognostic utility ascribed to M0 No evidence of involvement of other extranodal M0 size and location of ocular adnexal lym- sites (no pathologic M0; use clinical M to complete stage group) phoma was eclipsed by histological classi- 42 M1a Noncontiguous involvement of tissues or M1a fication and type of treatment. The capa- organs external to the ocular adnexa (eg, parotid bility of the TNM system to predict worse glands, submandibular gland, lung, liver, spleen, outcomes appears to reside in its ability to kidney, breast) identify bilateral disease and to delineate M1b Lymphoma involvement of the bone marrow M1b nodal and metastatic involvement at the M1c Both M1a and M1b M1c time of presentation.39,40 TNM = tumor, node, metastasis. The full potential of the TNM system Adapted from Edge S, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. may not be realized until it is modified to 7th ed. New York: Springer; 2010. Republished with permission of Springer; permis- include additional biomarkers and when sion conveyed through Copyright Clearance Center, Inc.

142 Cancer Control April 2016, Vol. 23, No. 2 new imaging technologies can be used to help pro- 5 cases of conjunctival extranodal marginal zone B-cell vide superior metrics in terms of tumor location and lymphomas using PCR amplification and Southern volume. blot hybridization. The DNA of H pylori was not found in normal conjunctiva from the same study patients.48 Pathogenesis The same group examined 8 study patients with or- Infectious agents have been suspected in the etiology bital extranodal marginal zone B-cell lymphoma and of extranodal marginal zone B-cell lymphoma of the found 1 study patient with the genomic fingerprints of ocular adnexa based on the causative role that Helico- H pylori.49 C pneumoniae (but not C psittaci or C tracho- bacter pylori infection plays in gastric MALT-type lym- matis) was identified in another.49 phoma.43 The progression of H pylori–induced chronic Lee et al 50 identified DNA of H pylori in gastritis to extranodal marginal zone B-cell lymphoma 15 of 15 cases of extranodal marginal zone B-cell is comprehensible both in terms of light microscopy lymphoma of the conjunctiva that they examined; no and molecular changes.43 Unlike malignant transfor- such discovery was made in the control group (n = 8). mation of lymphocytes through the direct infection of These findings contrast with another study involving lymphotropic viruses like Epstein–Barr virus or human 13 cases of extranodal marginal zone B-cell lympho- T-cell leukemia virus type 1, H pylori indirectly acts by ma of the conjunctiva in which H pylori DNA could not inducing chronic inflammation. This antigen-driven be detected in any tumor (either using immunohisto- process, coupled with other oncogenic events, can lead chemistry or PCR).51 to the emergence of antigen-independent lymphocyte The prevalence of gastric H pylori infection at the proliferation. time of initial diagnosis of extranodal marginal zone B-cell lymphoma varies between where the primary Chlamydia psittaci site of lymphoma is located.52 For example, the prev- The search for putative infectious agents for periocular alence rate of infection was found to be 45% (37 of lymphoma has resulted in conflicting results.44-47 Using 83 cases) in extranodal marginal zone B-cell lympho- PCR, an Italian study found that 80% of patients with ma of the ocular adnexa compared with 25% (25 of extranodal marginal zone B-cell lymphoma of the ocu- 101 cases) in extranodal marginal zone B-cell lympho- lar adnexa were exposed to Chlamydia psittaci.46 How- ma located elsewhere (but not the stomach).52 The rate ever, similar investigations from other regions of the of prevalence was 12% (18 of 156) among control cases world could not duplicate these results.44,47 In a review without lymphoma.52 These findings led investigators of 11 international studies, the overall rate of Chla- to propose another pathogenic mechanism involving mydia positivity in extranodal marginal zone B-cell the attraction of circulating lymphomatous cells to the lymphoma of the ocular adnexa was 23%, with the vast ophthalmic mucosa: Once around the eye, the lympho- majority of all positive cases (90%) occurring in 3 coun- cytes would then be transformed under the influence tries.47 In a survey of 423 cases of extranodal marginal of additional mitogenic stimuli.52 This study and the zone B-cell lymphoma of the ocular adnexa, the detec- proposed hypothesis has generated need for further tion rate of Chlamydia ranged from 0% to 87%, with investigation.52,53 seemingly inconsistent geographic variation.44 To control for spurious laboratory results, investigators used a Other Infectious Agents single standardized procedure for Chlamydia DNA de- An international study investigating the presence of tection among 142 cases of extranodal marginal zone viral DNA for herpes simplex virus types 1 and 2 and B-cell lymphoma of the ocular adnexa.45 The results adenovirus types 8 and 19 in persons with extranodal confirmed a variation in prevalence (eg, 11% in south- marginal zone B-cell lymphoma of the ocular adnexa ern China, 47% in Germany); the overall prevalence found no association.45 Although the conceptual model of C psittaci DNA was 22%, which was more than of an infectious etiology is appealing, consistent and twice the control group (10%; P = .04).45 However, reproducible evidence supporting any specific patho- based on historical prevalence, this result was not gen has been elusive.54,55 much greater than that established for non-neoplastic disorders of the orbit.44 Autoimmunity The possibility of an autoantigenic stimulus is sup- Helicobacter pylori ported by the association of extranodal marginal zone The causal association between H pylori infection B-cell lymphoma of the ocular adnexa with various au- and gastric extranodal marginal zone B-cell lympho- toimmune disorders (eg, Sjögren disease, Hashimoto ma is well established, so investigators have begun disease, IgG4-related disorder).56 The connection be- searching for a link between the bacterium and ex- tween Sjögren disease and lymphoma has been known tranodal marginal zone B-cell lymphoma of the ocular since the 1970s.57 Although Sjögren disease conveys a adnexa.48,49 Chan et al48 described H pylori DNA in 4 of 14-fold greater risk of B-cell lymphoma, the cause for

April 2016, Vol. 23, No. 2 Cancer Control 143 this susceptibility is unclear.57 Several cases of extrano- Chemotherapy dal marginal zone B-cell lymphoma of the ocular ad- Use of chemotherapy for local ocular adnexal disease nexa have been reported in persons with IgG4-related has been studied in 2 centers (n = 54); of the patients disease — an association that provides little additional studied, 52 had stage 1E disease (Table 3).61,67-69 Among insight into pathogenesis.58 21 study patients (19 [90%] with stage 1E) treated with cyclophosphamide, vincristine, and prednisolone, CR Treatment was reported in 16 (76%), local relapse occurred in 5, A comprehensive review of treatment options for ex- and systemic relapse occurred in 2; no deaths were re- tranodal marginal zone B-cell lymphoma of the ocu- ported during a median follow-up time of 55 months.68 lar adnexa is beyond the scope of this review. Most The other trial studied chlorambucil in 33 participants therapeutic studies have consisted of retrospective with stage 1E extranodal marginal zone B-cell lympho- case series.30,58-79 Comparing clinical outcomes in these ma.69 During a median follow-up of 26 months, CR was nonrandomized trials is perilous for several reasons. reported in 26, local recurrence in 1, and systemic re- Clinical series of ocular adnexal lymphoma published lapse in 3; 1 tumor-related death was noted.69 prior to 2000 often lumped extranodal marginal zone Proponents of initial chemotherapy state that this B-cell lymphoma together with other low-grade lym- treatment option eliminates local complications from phomas and atypical lymphoid hyperplasia.5 Even radiotherapy, such as dry eyes, cataracts, and skin ir- large studies involving 2 or more treatment arms had ritation, and is associated with fewer serious complica- limited statistical power to exclude small but mean- tions.68 Direct comparison with radiotherapy for stage ingful differences in outcome.5,8,15,30 The success of 1E disease is methodologically problematic, because local therapy is often confounded by supplemental some reports include small proportions of study pa- treatment given to partial responders because clinical tients with more advanced disease.68 The collective outcomes are collectively reported.5,8,15,30 In addition, rate of systemic relapse for radiotherapy is 6.2%, which short-term studies (< 5 years) may also not adequately is less than that currently reported for chemotherapy reflect the biological potential of the disease, particu- (9.3%; see Tables 2 and 3).61,64,69,70,73,79-84 larly in terms of rates of local and systemic recurrence, and tumor-related mortality. Immunotherapy Rituximab, a chimeric mouse antihuman CD20 mono- Radiotherapy clonal antibody, has been used as treatment for lym- Typically, radiotherapy results in a high rate of local phoma localized to the ocular adnexa.74 Two reports control that ranges from 85% to 100%, even in the involving 12 study patients with localized extrano- presence of systemic disease.59,60,62,64,73,75,76,79-83 Since dal marginal zone B-cell lymphoma have been pub- 2000, a total of 9 studies have examined the out- lished (see Table 3).61,67-69 In one study, 11 eyes of come of radiotherapy for localized extranodal mar- 10 study patients with ocular adnexal lymphoma were ginal zone B-cell lymphoma of the ocular adnexa treated with systemic rituximab.61 CR was reported in (Table 2).64,70,73,79-84 Some included small numbers 5 (56%; median follow-up of 31 months) without sys- of study patients with systemic disease, and clini- temic or ocular adverse events, and no tumor-related cal outcomes were measured in ways that pro- deaths were reported.61 The remaining study patients hibit uniform summarization. The majority of the required radiotherapy.61 Another report involved 503 study patients with stage 1E disease achieved 5 study patients with extranodal marginal zone B-cell local control.64,70,73,79-84 When reported, complete re- lymphoma of the ocular adnexa, 3 of whom had stage sponse (CR) rates ranged from 52% to 93%, whereas 1E disease.67 Four of the 5 study patients who initially the proportion of 5-year, systemic-free relapse rates responded to treatment locally relapsed.67 usually exceeded 90%.64,70,73,79-84 Overall, systemic To date, rituximab has been reported in relatively relapses occurred in 31 study patients (6.2%), rang- few patients with extranodal marginal zone B-cell lym- ing from a low rate of 2.2% (median follow-up of phoma localized to the ocular adnexa, with seemingly 32 months) to a high rate of 16.8% (median follow-up high rates of inadequate periocular response and local of 5.9 years).64,70,73,79-84 recurrence (see Table 3).61,67-69 The median follow-up However, these results must be interpreted with times (< 31 months) are too short to assess the role of caution because the methods and rigor used to detect rituximab as therapy for local disease at this time.61,67-69 recurrent disease differed and the protocols employed to treat partial response and recurrence varied. The Antibiotic Therapy different types of second-line therapies for incomplete Because some cases of extranodal marginal zone B-cell localized responses confound the direct comparison of lymphoma of the ocular adnexa have been associated clinical series, particularly in terms of rates of systemic with C psittaci infection, treatment with doxycycline recurrence and tumor-related deaths. has been attempted.47 A meta-analysis of 4 treatment

144 Cancer Control April 2016, Vol. 23, No. 2 Table 2. — Radiotherapy for Localized Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexaa Study No. of Location Stage Local Cases of Median Other No. of Study Relapseb Systemic Follow-Up Outcome Tumor- Patients Relapse Measure Related Deaths Goda80 89 Conjunctiva: 59 1E: 89 7 15 5.9 y 7-y relapse-free 3 Lacrimal gland: 20 survival: 64% Orbit: 10 Hashimoto70 78 Conjunctiva: 37 1E: 78 66 mo 5-y PFS: 86% None Orbit: 29 10-y OS: 95.3% Lacrimal gland: 12 Le84 31 Conjunctiva: 21 1E: 31 None 5 5.9 y 100% local 1 Orbit: 10 Bilateral: 4 (range, control 0.75–20.3) Nam73 66 Conjunctiva: 29 1E: 66 Conjunctiva: 2 3 50 mo 5-y systemic None Orbit: 20 Bilateral: 14 Orbit: 0 (range, relapse-free 12–114) survival: 95.4% Lacrimal gland: 7 Lacrimal Eyelid: 10 gland: 2 Eyelid: 2 Son82 46 Conjunctiva: 37 1E: 46 1 1 32 mo CR with 5-y None Eyelid: 3 Bilateral: 3 (range, relapse-free 3–114) survival: 93% Orbit: 6 Suh83 48 “Orbit” 1E: 46 3 None 39–72 mo 10-y relapse- 1c Bilateral: 4 free survival: 93% IV: 2 Tran81 24 Conjunctiva: 16 1E: 22 2 1 41 mo PFS: 90% 1 case of Orbit: 3 Bilateral: 3 (range, 5-y OS: 100%d high-grade 5–137) lymphoma Lacrimal gland: 7 IV: 2 Eyelid: 1 Uno64 50 Conjunctiva: 29 1E: 50 3 3 46 mo CR: 26 1 Orbit: 17 Bilateral: 7 (range, PR: 20 10–140) Eyelid: 2 No response: 4 Lacrimal gland: 2 Woolf79 71 + 10 low- Orbit: 56 1E: 81 None Distant: 3 4.4 y 100% local None e grade lym- Conjunctiva: 14 Bilateral: 4 Contralateral (range, control phomas 0.2–10.4) Lacrimal gland: 11 lacrimal gland (local): 1 Eyelid: 4

Totalf 503 499 6 (1.2%)g aIncludes series since 2000 with 85% or more localized cases of stage 1E disease. bLocal relapse defined as any portion of ocular adnexa, including the contralateral side, of initial unilateral disease. cTumor death occurred in 1 study patient with stage IV disease. dHigh-grade lymphoma death occurred at 71 mo. eOf the 81 original study patients, 71 (88%) had extranodal marginal zone B-cell lymphoma. fData not sufficiently detailed to provide totals for local and systemic relapses. gPercentage based on study patients with stage 1E disease. CR = complete response, OS = overall survival, PFS = progression-free survival, PR = partial response. trials taking place prior to 2006 totaling 42 study pa- of predominantly primary extranodal marginal zone tients found that 20 responded to oral antibiotics, B-cell lymphoma localized to the ocular adnexa in 20 remained stable, and 2 progressed.47 Although CR 151 study patients (Table 4).76,78,85-87 Because the rate was reported in 8 study patients, objective respons- of tumor response (ie, reduction in size) differs fol- es with radiography or slit lamp photography were lowing treatment with doxycycline and radiotherapy available in 3.47 or chemotherapy, it is difficult to directly measure and Since 2006, researchers have initiated 3 trials to compare clinical outcomes.78,85,87 One study reported a study the effect of doxycycline on the management 2-year failure-free survival rate of 67%,85 whereas an-

April 2016, Vol. 23, No. 2 Cancer Control 145 Table 3. — Chemotherapy or Immunotherapy for Localized Extranodal Marginal Zone Lymphoma of the Ocular Adnexaa Study Treatment No. of Location Stage Cases Cases of Median Other No. of Study of Local Systemic Follow- Outcome Tumor- Patients Relapseb Relapse Up, mo Measures Related Deaths Chemotherapy Ben Chlorambucil 33 Orbit: 10 1E: All 1 3 26 (range, CR: 26 1 Simon69 Lacrimal gland: 8 8–62) Conjunctiva: 7 Eyelid: 6 Combination: 2 Song68 Cyclophosphamide 21 Conjunctiva: 6 1E: 19 5 2 58 (range, CR: 16 None Vincristine Orbit: 8 Bilateral: 2 6–163) PR: 5 Prednisolone Eyelid: 5 IIE: 2 Lacrimal gland: 2 Adnexa (general): 2 Immunotherapy Ferreri67 Rituximab 5 Conjunctiva: 2 1E: 3 4 1 23 (range, None Orbital: 1 IV: 2 2–4) Tuncer61 Rituximab 9 Conjunctiva: 5 1E: All 6 None 31 (range, CR: 5 None Bilateral: 1 10–61) PR: 4 Orbit: 4 aIncludes series with ≤ 2 study patients with disease beyond the orbit. bLocal relapse defined as any portion of ocular adnexa, including the contralateral side, of initial unilateral disease. CR = complete response, PR = partial response.

Table 4. — Antibiotic Therapy or Observation for Extranodal Marginal Zone Lymphoma of the Ocular Adnexaa Study Treatment No. of Location Stage Cases Cases of Median Other No. of Study of Local Systemic Follow-Up Outcome Tumor- Patients Relapseb Relapse Measures Related Deaths Antibiotic Therapy Ferreri85 Doxycycline 27 Conjunctiva: 14 1E: 24 Unable to determine 21 mo Overall None Orbit: 13 IIE: 3 local from systemic (range, response: 64% relapses 4–204) Bilateral: 5 2-y failure-free survival: 67% Ferreri87 Doxycycline 34 Conjunctiva: 23 1E: All 14 failures 37 mo 5-y PFS: 55% None Orbit: 14 Unable to delineate (range, 15–62) Lacrimal gland: 5 local from systemic Conjunctiva/orbit: 5 Han78 Doxycycline 90 Conjunctiva: 74 T1N0M0: 62 31 6 40.5 mo 5-y PFS: 61% None Orbit: 12 T2N0–2 M0: 22 (range, 8–85) Eyelid: 3 T3N0–2 M0: 5 Lacrimal gland: 2 T4N0M0: 1 Observation Without Treatment Matsuo76 None other 8c Conjunctiva: 8 1E: All None None 5.4 y 7 sponta- None than biopsy (range, neously 1–11) regressed Tanimoto86 None other 36 Conjunctiva: 15 1E: 36 15 2 10.5 y OS: 2 c than biopsy Orbit: 19 Bilateral: 5 (range, 5-y: 94% 0.7–16.7) Lacrimal gland: 2 10-y: 94% 15-y: 71% aIncludes series with ≥ 85% localized stage 1E extranodal marginal zone B-cell lymphoma since 2000. bLocal relapse defined as any portion of the ocular adnexa, including the contralateral side, of initial unilateral disease. cEight of 13 study patients who declined treatment and are the focus of this review. OS = overall survival, PFS = progression-free survival.

146 Cancer Control April 2016, Vol. 23, No. 2 other series reported that the failure-free survival rate tion to high-grade lymphoma occurred in 1 case.76,86 after 5 years was 55%.87 Progressive disease was treat- The majority of tumors arose in conjunctiva (23 [52%]), ed with a variety of traditional protocols, and no tu- 7 of which spontaneously regressed.76,86 Therefore, the mor-related deaths were reported (see Table 4).76,78,85-87 study authors concluded that watchful waiting might In that study, patients were excluded from the trial if be an acceptable option in select patients with unilat- they had large tumors or tumors demonstrating rapid eral extranodal marginal zone B-cell lymphoma of the growth.87 Because criteria describing large tumor size ocular adnexa.86 and rapid growth were not provided, an exclusion bias of unknown clinical importance complicates any in- Assessment of Clinical Outcome terpretation of these results.87 Comparing the treatment of primary lymphoma local- Long-term follow-up in 1 study of 90 patients ized to the ocular adnexa is difficult because some se- initially treated with doxycycline had mixed re- ries combine different histological types of lymphoma, sults.78 Patients enrolled in the clinical trial received some researchers do not separately analyze for ana- twice-daily oral 100 mg doxycycline for either 3 or tomical subgroups (eg, conjunctiva, orbit), and some 6 weeks and were followed for a mean time of 40.5 report clinical outcomes differently. In addition, not months.78 A total of 61% had no progression after 5 all studies employ standardized intervals for follow- years, and 34 study patients who failed doxycy- up or methods for monitoring outcome (eg, CT, MRI, cline therapy were successfully managed with che- PET/CT, PET). Few provide information on primary tu- motherapy, radiotherapy, or both.78 No tumor-re- mor size, and most employ different salvage therapies lated deaths were reported; systemic relapse was for partial responders. reported in 6 study patients.78 Pretreatment exposure to Tumor size is an important parameter to moni- C psittaci was not determined. tor because the rapidity and completeness with “Failed to progress” reports are difficult to com- which a tumor shrinks may correlate with durabil- pare to studies whose benchmark outcomes are either ity of response.89 However, the speed at which tumor complete or partial regression, and this is particularly size is reduced may be of less importance in cases of true for cases of lymphoma with an indolent course. low-grade lymphoma compared with other neoplasms, Lacking or incomplete knowledge of a history of chla- and it may be of less value in terms of assessing anti- mydial infection among patients enrolled in antibiotic biotic effectiveness. Use of tumor diameter — not vol- studies further complicates interpretation, because the ume — as an outcome variable for extranodal marginal global variation in C psittaci infection rate should affect zone B-cell lymphoma of the ocular adnexa reflects the response rate to doxycycline. Future trials of antibi- how difficult it is to obtain reliable volumetric data on otic treatment may be more efficient if their enrollment periocular tumors in general. is appropriately limited to patients with documented Measuring the volume or planar dimensions of exposure to C psittaci. periocular tumors presents unique challenges. For ex- A 6-month trial of a second-line therapeutic agent, ample, oftentimes, lymphomas of the ocular adnexa clarithromycin, was reported in a trial of 7 study vol- are irregularly shaped and conform to the contours of unteers who had extranodal marginal zone B-cell lym- the eye and orbital walls. It might be valuable to ap- phoma that failed to respond to doxycycline.88 Partial ply the Response Evaluation Criteria in Solid Tumors response was reported in 4 study patients and stable (RECIST) and RECIST 1.1 to these lesions, but these disease for varying periods of time was reported in 3; criteria have not been independently validated in the however, all study patients experienced disease pro- context of low-grade lymphoma of the ocular adnexa.89 gression (average time to progression, 16 months).88 One of the few studies that addressed the role of quantitative, monitored outcomes in the setting of ex- Observation tranodal marginal zone B-cell lymphoma of the ocu- Given the indolent nature of extranodal marginal zone lar adnexa following radiotherapy was performed by B-cell lymphoma of the ocular adnexa, some investi- Jung et al.90 These researchers found that the maxi- gators have wondered whether observation may be a mum tumor diameter decreased by 50% of its initial viable option, particularly in persons of advanced age size after 4.7 months of treatment.90 The authors em- or with other comorbidities that may limit survival.76,86 phasize that partial and total responses are usually Two groups reported on the long-term follow-up data poorly defined in most clinical series — both in terms of 44 study patients with localized disease (5 bilater- of tumor-specific size reductions and in follow-up in- al); the median follow-up periods were 5.4 years76 and tervals after treatment.90 10.5 years.86 Twenty-five (57%) study patients did not require treatment throughout the course of the study, Conclusions and 2 succumbed to progressive lymphoma.76,86 A Extranodal marginal zone B-cell lymphoma of the ocu- total of 17 study patients (39%) progressed; transforma- lar adnexa can arise in the setting of reactive lymphoid

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