From the Departments of Pathology (SF, SSG), Ophthalmology and Visual Science (NA, MGW), and Pediatrics (MLS), University of Illinois at Chicago, Chicago, Illinois.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Mary Lou Schmidt, MD, Department of Pediatrics (MC 856), University of Illinois at Chicago, 1347 CSB, 840 S. Wood Street, Chicago, IL 60612.
Ocular adnexal lymphoma arises in the conjunctiva, orbit, eyelid, lacrimal gland, or lacrimal sac.1 It comprises 2.5% of extranodal non-Hodgkin lymphomas,2 and is most commonly a marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).3 Both sexes are equally affected, and the prevalence according to race increases from Asians/Pacific Islanders to whites to African Americans.2 The lymphoma can spread outside the orbit, and was found to do so in 50% of less differentiated ocular adnexal lymphoma; nevertheless, no extraorbital disease occurred in well-differentiated monoclonal ocular adnexal lymphoma tumors.4
Mean age at diagnosis is 63 years, with ocular adnexal lymphoma rarely reported in the pediatric population.3 In a summary of 353 cases of ocular adnexal lymphoma, only 5 patients (1.4%) younger than 21 years were found.1 There are several case reports in the literature that describe characteristics of ocular adnexal lymphoma in the pediatric population,5 but none addresses the issue of treatment. Given the risk of late effects, such as extraorbital extension, careful consideration of treatment options for pediatric ocular adnexal lymphoma must be conducted.
Treatment recommendations for ocular adnexal lymphoma usually include surgical excision of the primary tumor, with or without cryotherapy,6 followed by either radiotherapy,7 chemotherapy,8 and, more recently, anti-CD20 monoclonal antibody (Rituximab; Genentech, San Francisco, CA),9,10 intralesional injections of interferon-alpha,11 or the antibiotic doxycycline.12 We describe the clinicopathologic course of a 13-year-old boy, including treatment options for pediatric ocular adnexal lymphoma.
A 13-year-old boy presented with a 4-week history of painless irritation of the right eye, inability to close his eye, and blurred vision due to a rapidly growing pink fleshy mass over the nasal bulbar conjunctiva adjacent to the caruncle (Fig. 1A). Ocular examination was normal except for the 8-mm pedunculated lesion with a narrow base that extended from the caruncle to 1 mm away from the limbus (Figs. 1B and 1C). Initial treatment included tobramycin 0.3%–dexamethasone 0.1% ointment four times a day for suspected conjunctivitis.
Figure 1. Clinical Photographs of the Conjunctival Lesions. (A) the Main Lesion on the Right Eye Nasal Conjunctiva and the Small Lesion on the Left Eye Nasal Conjunctiva. (B) Intraoperative Photograph of the Right Eye Conjunctival Lesion. (C) the Lesion Has a Narrow Base and Is not Attached to Most of the Bulbar Conjunctiva.
Within 5 days of presentation, magnetic resonance imaging of the brain identified a moderately enhancing solid mass arising from the conjunctiva immediately anterior to the insertion of the medial rectus muscle, not involving the globe or the medial rectus muscle. A small pharyngeal mass was identified and initially assessed as a sign of an upper respiratory tract infection. By 4 weeks from initial presentation, the lesion enlarged to 9 mm in diameter and a similar lesion appeared in a mirror location on the left eye.
The right eye lesion was excised and measured 12.0 × 8.0 × 5.0 mm. Histopathology identified a dense lymphoid infiltrate and occasional residual follicles with run-over germinal centers (Fig. 2A). Neoplastic cells were small with relatively abundant pale cytoplasm and a “monocytoid” appearance (Fig. 2B). They expressed CD20 (Fig. 2C), CD79a, and BCL2, and were negative for CD5, CD10, CD43, and cyclin D1. CD3 (Fig. 2D), CD5, and CD43 highlighted background T-cells. The final diagnosis was low-grade B-cell lymphoma, most consistent with extranodal marginal zone B-cell non-Hodgkin lymphoma. The tissue did not yield DNA of good enough quality for polymerase chain reaction analysis for Chlamydia.
Figure 2. Photomicrographs of the Right Eye Conjunctival Lesion. (A) Entire Section Stained with Hematoxylin–Eosin (original Magnification ×1, Bar = 500 μm). (B) the Conjunctival Substantia Propria Is Full of Lymphocytes (original Magnification ×20, Bar = 50 μm). (C) an Almost Uniform, Strong Positive Stain in the Conjunctival Substantia Propria with Cd20 Immunostain (original Magnification ×1, Bar 500 = μm). (D) a Patchy, Weak Stain with CD3 Immunostain, Complementing the CD20 Staining in C (original Magnification ×1, Bar = 500 μm).
Positron emission tomography–computed tomography did not identify any extension into the orbit, and computed tomography scan of the neck, chest, abdomen, and pelvis did not identify evidence of primary or metastatic disease. A course of 4 weekly intravenous injections of Rituximab was initiated, which required pretreatment with diphenhydramine, acetaminophen, and methylprednisolone (1 mg/kg) due to an allergic reaction. Subsequent Rituximab injections were uneventful with similar pretreatment medications. The conjunctival lesion in the left eye was not biopsied and gradually receded. The pharyngeal mass that was identified in the initial imaging regressed dramatically after treatment, but it remains unclear whether this represented lymphomatous involvement or an upper respiratory tract infection. No recurrence was identified in 14 months of follow-up.
In adults, treatment of ocular adnexal lymphoma generally includes primary surgical excision of the tumor (with or without cryotherapy),6 usually followed by additional adjuvant therapy (most commonly radiation therapy). In selected cases in which the tumor appears to have been completely excised, cryotherapy to the tumor’s bed can be added and the patient can be observed with no additional therapy. However, in most cases the tumor extends into the orbit and cannot be completely excised. Radiation therapy is also used for extensive unresectable disease. The great majority of patients survived without relapse when treated with a combination of excision and irradiation,7 which commonly leads to dryness, corneal ulceration, damage to the retina, and cataract.13
These side effects, which may be acceptable in the adult population, would be deleterious in the pediatric group, especially because children cannot be relied on to self-administer lubrication drops. Untreated corneal dryness would lead to abrasions, ulcerations, and eventually scarring and blindness. Chemotherapy such as cyclophosphamide, vincristine, and prednisolone8 instead of radiation has also been used in adults with less impressive results. Alternative treatment approaches include chlorambucil with Rituximab (remission rate: 89% in 8 of 9 patients9; Rituximab alone (remission rate: 5 of 5 newly diagnosed patients)10; intralesional injections of interferon-alpha11; and doxycycline (regression rate of 64% of Chlamydia psittaci–positive cases).14 Doxycycline was used after C. psittaci was identified as a possible infectious cause for this malignancy.12 All studies include very small numbers.
In contrast with gastric lymphoma, in which a strong correlation was found with the presence of Helicobacter pylori,15 there are only a few publications that reported this pathogen in ocular adnexal lymphoma specimens.16C. psittaci infection was detected in only 11% of patients with stage I lymphoma; thus, doxycycline is a valid therapeutic alternative only in a limited selection of patients with ocular adnexal lymphoma with disseminated disease.12 Our patient initially received topical therapy with a tetracycline, which may have reduced the chances to detect C. psittaci infection.
No published reports exist regarding the C. psittaci infection status of children with ocular adnexal lymphoma. With no evidence for infection or disseminated disease, no systemic antibiotics were offered in our case. Recent observations in several European centers have found that there is a high rate of local recurrence after treatment with doxycycline (members of the 2009 spring meeting of the Ocular Oncology Group, Jerusalem, Israel, oral communication, April 2009). Nevertheless, because this treatment modality is the least toxic of all options and has not been tested in children yet, C. psittaci testing should be performed for all patients with ocular adnexal lymphoma, including children.
Conventional treatment by local resection and radiation therapy may be inadequate in children. Orbital radiation therapy is discouraged in patients younger than 1 year to prevent bony deformities of the face. In the current case, radiation therapy to both eyes would have increased the risk of late effects and would have not managed any possible systemic disease. The conjunctiva of both eyes is considered one site; therefore, excising tissue from the left eye would have not altered the diagnosis. Had the diagnosis of ocular adnexal lymphoma been known in advance, resection of the left eye lesion may have been considered. However, the small size of the left eye lesion made it reasonable to rely on systemic treatment that was already required due to the bilaterality of the disease, thus preventing an additional general anesthesia procedure along with its risks. It is unclear whether the initial positron emission tomography–positive pharyngeal mass represented lymphoma or an upper respiratory tract infection; this would have changed the staging from Ann Arbor stage IAE to II, but not the decision to give systemic treatment.
Most ocular adnexal lymphomas are of B-cell lineage and express CD20, thus allowing monoclonal antibody therapy with a minimal risk of severe late effects. Rituximab was found to have significant activity in MALT lymphomas.17 In chemotherapy-naïve patients, it had an 87% response rate. The most common side effects were infusion-related side effects, including hypotension, angioedema, bronchospasm, skin rash, and fever. The majority of these events were of mild to moderate severity and self-limiting. In a phase II study,17 26% of patients relapsed. This is a higher relapse rate than that reported for gastric MALT lymphoma.10 In patients with B-cell lymphoma, Rituximab was added to the standard chemotherapy protocols to construct R-CHOP (Rituximab–cyclophosphamide, vincristine, doxorubicin, and prednisone). This combination may overcome the relapse rate of Rituximab alone, but in the pediatric population, one may wish to wait and see whether a relapse occurs because it may not occur in 75% of cases and thus the child may be spared the late effects of CHOP, including the risk of secondary malignancy, infertility, cardiomyopathy, and neuropathy.
No general recommendations can be made at this point regarding the treatment of ocular adnexal lymphoma in children. Treatment should be tailored to the extent of disease. C. psittaci testing should be performed. Data are lacking for the relapse rate of children treated with Rituximab alone, but given the 75% relapse-free survival rate in CD20+ non-Hodgkin lymphoma in children and adults and the absence of major complications, initial therapy with rituximab is warranted with close follow-up.
- Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol. 2007;31:170–184. doi:10.1097/01.pas.0000213350.49767.46 [CrossRef]
- Moslehi R, Devesa SS, Schairer C, Fraumeni JF Jr, . Rapidly increasing incidence of ocular non-Hodgkin lymphoma. J Natl Cancer Inst. 2006;98:936–939.
- Fung CY, Tarbell NJ, Lucarelli MJ, et al. Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes. Int J Radiat Oncol Biol Phys. 2003;57:1382–1391.
- Jakobiec FA, Iwamoto T, Knowles DM 2nd, . Ocular adnexal lymphoid tumors: correlative ultrastructural and immunologic marker studies. Arch Ophthalmol. 1982;100:84–98.
- Liang X, Stork LC, Albano EA. Primary ocular adnexal lymphoma in pediatric patients: report of two cases and review of the literature. Pediatr Dev Pathol. 2003;6:458–463. doi:10.1007/s10024-003-1003-7 [CrossRef]
- Eichler MD, Fraunfelder FT. Cryotherapy for conjunctival lymphoid tumors. Am J Ophthalmol. 1994;118:463–467.
- Baldini L, Blini M, Guffanti A, et al. Treatment and prognosis in a series of primary extranodal lymphomas of the ocular adnexa. Ann Oncol. 1998;9:779–781. doi:10.1023/A:1008327301372 [CrossRef]
- Song EK, Kim SY, Kim TM, et al. Efficacy of chemotherapy as a first-line treatment in ocular adnexal extranodal marginal zone B-cell lymphoma. Ann Oncol. 2008;19:242–246. doi:10.1093/annonc/mdm457 [CrossRef]
- Rigacci L, Nassi L, Puccioni M, et al. Rituximab and chlorambucil as firstline treatment for low-grade ocular adnexal lymphomas. Ann Hematol. 2007;86:565–568. doi:10.1007/s00277-007-0301-y [CrossRef]
- Ferreri AJ, Ponzoni M, Martinelli G, et al. Rituximab in patients with mucosal-associated lymphoid tissue-type lymphoma of the ocular adnexa. Haematologica. 2005;90:1578–1579.
- Lucas RS, Mortimore R, Sullivan TJ, Waldie M. Interferon treatment of childhood conjunctival lymphoma. Br J Ophthalmol. 2003;87:1191. doi:10.1136/bjo.87.9.1191 [CrossRef]
- Ferreri AJ, Dognini GP, Ponzoni M, et al. Chlamydia-psittaci-eradicating antibiotic therapy in patients with advanced-stage ocular adnexal MALT lymphoma. Ann Oncol. 2008;19:194–195. doi:10.1093/annonc/mdm561 [CrossRef]
- Stafford SL, Kozelsky TF, Garrity JA, et al. Orbital lymphoma: radiotherapy outcome and complications. Radiother Oncol. 2001;59:139–144. doi:10.1016/S0167-8140(00)00328-5 [CrossRef]
- Ferreri AJ, Ponzoni M, Guidoboni M, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multi-center prospective trial. J Natl Cancer Inst. 2006;98:1375–1382.
- Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994;330:1267–1271. doi:10.1056/NEJM199405053301803 [CrossRef]
- Chan CC, Shen D, Mochizuki M, et al. Detection of Helicobacter pylori and Chlamydia pneumoniae genes in primary orbital lymphoma. Trans Am Ophthalmol Soc. 2006;104:62–70.
- Conconi A, Martinelli G, Thieblemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003;102:2741–2745. doi:10.1182/blood-2002-11-3496 [CrossRef]