Clinical Review & Education
JAMA Ophthalmology Clinical Challenge
Diffusely Swollen Eyelid Qi N. Cui, MD, PhD; Michael J. Geske, MD; Robert C. Kersten, MD
B
C
F
G
A
D
E
Figure. A, Swollen right upper eyelid. Magnetic resonance images demonstrating diffuse eyelid infiltration (B, arrowhead) and lymphadenopathy (C, arrowhead). Biopsy of the eyelid lesion showing large atypical lymphocytes
on hematoxylin-eosin stain (D, original magnification ×400) that was positive for CD20 (E, original magnification ×100), negative for CD5 (F, original magnification ×100), and negative for Bcl-1 (G, original magnification ×100).
A 55-year-old man presented with diffuse, painful swelling of the right upper eyelid (Figure, A). The patient’s medical history was notable for rheumatoid arthritis that had been well controlled with methotrexate for 15 years. The lesion was first noted 6 months prior to presentation and was initially diagnosed as a chalazion. The nodule increased in size during the next several months Quiz at despite conservative measures including warm comjamaophthalmology.com presses. A biopsy revealed a mixed inflammatory infiltrate without evidence of neoplasia, supporting a diagnosis of chalazion. Intralesional triamcinolone was then administered. Despite an initial decrease in lesion size, 6 weeks postinjection, new-onset ipsilateral extraocular motility deficits and palpable preauricular lymphadenopathy were noted. A magnetic resonance image revealed an infiltrative process in the involved eyelid and lymphadenopathy (Figure, B and C). A second biopsy of the eyelid lesion revealed large, atypical lymphocytes diffusely positive for CD20 and negative for CD5 and Bcl-1 (Figure, D-G), supporting a diagnosis of diffuse large B-cell lymphoma (DLBCL). Findings from systemic evaluation, including complete blood cell count, serum protein electrophoresis, serum lactate dehydrogenase, and whole-body positron emission tomography, were unremarkable.
jamaophthalmology.com
WHAT WOULD YOU DO NEXT?
A. Initiate treatment with radiation and/or chemotherapy B. Initiate treatment with rituximab C. Excise the eyelid lesion D. Determine Epstein-Barr virus status and consider observation following cessation of methotrexate therapy
JAMA Ophthalmology September 2014 Volume 132, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
1145
Clinical Review & Education JAMA Ophthalmology Clinical Challenge
Diagnosis Methotrexate-associated lymphoma
What To Do Next D. Determine Epstein-Barr virus (EBV) status and consider observation following cessation of methotrexate therapy. A body of literature has emerged suggesting an association between EBV, rheumatoid arthritis (RA) treated with methotrexate, and non-Hodgkinlymphoma.1 Morethan50casesoflymphomahavebeen reportedinpatientswithRAtreatedwithmethotrexate.2,3 Epstein-Barr virus RNA has been found in 30% to 40% of patients with RA treated withmethotrexatewhodevelopedlymphoma.4,5 Mostimportantly,EBV positivity has been associated with spontaneous regression following cessation of methotrexate therapy.5 In patients with RA who develop methotrexate-associated lymphoma, there is evidence to support a management strategy consisting of assessment of EBV status and cessation of methotrexate therapy in EBV-positive cases, followed by an observation period of up to 2 months before initiation of cytotoxic therapy, radiation therapy, and/or anti-CD20 monoclonal antibody rituximab.1
Discussion Diffuse large B-cell lymphoma is the most common lymphoma subtype, and it is increasingly recognized as a heterogeneous disorder that exhibitsgreatmorphological,immunochemical,andgeneticdiversity.6 Diffuse large B-cell lymphoma of the ocular adnexa is relatively rare, accounting for only 8% to 13% of ocular adnexal lymphomas.6 B-cell lymphoma involvement of the eyelid is even less common, occurring only 6% to 10% of the time.6-8 Immunodeficiency is a known risk factor for the development of non-Hodgkin lymphoma and is frequently seen in patients with human immunodeficiency virus infection and immunosuppression in the setting of organ transplant or rheumatic disease. In this setting, nonHodgkin lymphoma is frequently associated with EBV infection. For example, in posttransplant lymphoproliferative disorders, 90% have been shown to be associated with EBV infection.9
Patient Outcome Methotrexate was discontinued at the advice of the patient’s rheumatologist. No other intervention or treatment was pursued. Following cessation of methotrexate therapy, the eyelid lesion and the preauricularlymphadenopathyrapidlyresolvedover2weeks,andnolocal or systemic recurrence was noted after 26 months of follow-up. Despite the clinical response to methotrexate withdrawal, the patient’s EBV status was assessed retrospectively and was negative. Long-term follow-up and vigilance for recurrence is warranted in patients like ours. Fewer than 20 cases of B-cell lymphoma involving the eyelids have been reported. To our knowledge, this is the first case of DLBCL of the eyelid that demonstrated spontaneous regression following cessation of immunosuppressive therapy. This case also highlighted the fact that in cases of recurrent chalazia—in addition to sebaceous carcinoma—lymphomatous infiltration should also be included in the differential diagnosis, especially in the setting of immunosuppression.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Ophthalmology, University of California, San Francisco, School of Medicine.
1. Starkebaum G. Rheumatoid arthritis, methotrexate, and lymphoma: risk substitution, or cat and mouse with Epstein-Barr virus? J Rheumatol. 2001;28(12):2573-2575.
Corresponding Author: Qi N. Cui, MD, PhD, Department of Ophthalmology, University of California, San Francisco, School of Medicine, 10 Koret St, K304 San Francisco, CA 94143-0730 ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was made possible in part by National Institutes of Health–National Eye Institute EY002162 Core Grant for Vision Research and by a Research to Prevent Blindness unrestricted grant. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
1146
Epstein-Barr virus has also been implicated in lymphoma occurring in patients with RA treated with long-term methotrexate therapy. Waldman and Callen4 reviewed 13 cases of lymphoma associated with methotrexate and found that 9 patients were EBV positive. In this subgroup, 8 of 9 cases demonstrated complete resolution following methotrexate discontinuation. Following methotrexate withdrawal, spontaneous tumor regression has been reported in up to 59% of patients with methotrexate-associated lymphomas, with complete remission generally occurring within 4 weeks.10 Owing to the high rate of spontaneous regression, rheumatologists and oncologists often observe methotrexateassociated lymphoproliferative lesions following cessation of immunosuppression rather than immediately starting chemotherapy and external beam radiotherapy. An observation period of up to 2 months following cessation of methotrexate before initiating lymphoma treatment has been advocated.
2. Georgescu L, Paget SA. Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf. 1999;20(6): 475-487. 3. van de Rijn M, Cleary ML, Variakojis D, Warnke RA, Chang PP, Kamel OW. Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis. Arthritis Rheum. 1996;39(4): 638-642. 4. Waldman MA, Callen JP. Self-resolution of Epstein-Barr virus-associated B-cell lymphoma in a patient with dermatomyositis following withdrawal of mycophenolate mofetil and methotrexate. J Am Acad Dermatol. 2004;51(2)(suppl):s124-s130. 5. Salloum E, Cooper DL, Howe G, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol. 1996;14(6):1943-1949.
6. Rasmussen PK, Ralfkiaer E, Prause JU, et al. Diffuse large B-cell lymphoma of the ocular adnexal region: a nation-based study. Acta Ophthalmol. 2013;91(2):163-169. 7. Knowles DM, Jakobiec FA, McNally L, Burke JS. Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987. Hum Pathol. 1990;21(9):959-973. 8. Meunier J, Lumbroso-Le Rouic L, Vincent-Salomon A, et al. Ophthalmologic and intraocular non-Hodgkin’s lymphoma: a large single centre study of initial characteristics, natural history, and prognostic factors. Hematol Oncol. 2004;22(4):143-158. 9. Knowles DM. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol. 1999;12 (2):200-217. 10. Ichikawa A, Arakawa F, Kiyasu J, et al. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 2013;91(1):20-28.
JAMA Ophthalmology September 2014 Volume 132, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
jamaophthalmology.com
JAMA Ophthalmology Clinical Challenge
Diffusely Swollen Eyelid Qi N. Cui, MD, PhD; Michael J. Geske, MD; Robert C. Kersten, MD
B
C
F
G
A
D
E
Figure. A, Swollen right upper eyelid. Magnetic resonance images demonstrating diffuse eyelid infiltration (B, arrowhead) and lymphadenopathy (C, arrowhead). Biopsy of the eyelid lesion showing large atypical lymphocytes
on hematoxylin-eosin stain (D, original magnification ×400) that was positive for CD20 (E, original magnification ×100), negative for CD5 (F, original magnification ×100), and negative for Bcl-1 (G, original magnification ×100).
A 55-year-old man presented with diffuse, painful swelling of the right upper eyelid (Figure, A). The patient’s medical history was notable for rheumatoid arthritis that had been well controlled with methotrexate for 15 years. The lesion was first noted 6 months prior to presentation and was initially diagnosed as a chalazion. The nodule increased in size during the next several months Quiz at despite conservative measures including warm comjamaophthalmology.com presses. A biopsy revealed a mixed inflammatory infiltrate without evidence of neoplasia, supporting a diagnosis of chalazion. Intralesional triamcinolone was then administered. Despite an initial decrease in lesion size, 6 weeks postinjection, new-onset ipsilateral extraocular motility deficits and palpable preauricular lymphadenopathy were noted. A magnetic resonance image revealed an infiltrative process in the involved eyelid and lymphadenopathy (Figure, B and C). A second biopsy of the eyelid lesion revealed large, atypical lymphocytes diffusely positive for CD20 and negative for CD5 and Bcl-1 (Figure, D-G), supporting a diagnosis of diffuse large B-cell lymphoma (DLBCL). Findings from systemic evaluation, including complete blood cell count, serum protein electrophoresis, serum lactate dehydrogenase, and whole-body positron emission tomography, were unremarkable.
jamaophthalmology.com
WHAT WOULD YOU DO NEXT?
A. Initiate treatment with radiation and/or chemotherapy B. Initiate treatment with rituximab C. Excise the eyelid lesion D. Determine Epstein-Barr virus status and consider observation following cessation of methotrexate therapy
JAMA Ophthalmology September 2014 Volume 132, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
1145
Clinical Review & Education JAMA Ophthalmology Clinical Challenge
Diagnosis Methotrexate-associated lymphoma
What To Do Next D. Determine Epstein-Barr virus (EBV) status and consider observation following cessation of methotrexate therapy. A body of literature has emerged suggesting an association between EBV, rheumatoid arthritis (RA) treated with methotrexate, and non-Hodgkinlymphoma.1 Morethan50casesoflymphomahavebeen reportedinpatientswithRAtreatedwithmethotrexate.2,3 Epstein-Barr virus RNA has been found in 30% to 40% of patients with RA treated withmethotrexatewhodevelopedlymphoma.4,5 Mostimportantly,EBV positivity has been associated with spontaneous regression following cessation of methotrexate therapy.5 In patients with RA who develop methotrexate-associated lymphoma, there is evidence to support a management strategy consisting of assessment of EBV status and cessation of methotrexate therapy in EBV-positive cases, followed by an observation period of up to 2 months before initiation of cytotoxic therapy, radiation therapy, and/or anti-CD20 monoclonal antibody rituximab.1
Discussion Diffuse large B-cell lymphoma is the most common lymphoma subtype, and it is increasingly recognized as a heterogeneous disorder that exhibitsgreatmorphological,immunochemical,andgeneticdiversity.6 Diffuse large B-cell lymphoma of the ocular adnexa is relatively rare, accounting for only 8% to 13% of ocular adnexal lymphomas.6 B-cell lymphoma involvement of the eyelid is even less common, occurring only 6% to 10% of the time.6-8 Immunodeficiency is a known risk factor for the development of non-Hodgkin lymphoma and is frequently seen in patients with human immunodeficiency virus infection and immunosuppression in the setting of organ transplant or rheumatic disease. In this setting, nonHodgkin lymphoma is frequently associated with EBV infection. For example, in posttransplant lymphoproliferative disorders, 90% have been shown to be associated with EBV infection.9
Patient Outcome Methotrexate was discontinued at the advice of the patient’s rheumatologist. No other intervention or treatment was pursued. Following cessation of methotrexate therapy, the eyelid lesion and the preauricularlymphadenopathyrapidlyresolvedover2weeks,andnolocal or systemic recurrence was noted after 26 months of follow-up. Despite the clinical response to methotrexate withdrawal, the patient’s EBV status was assessed retrospectively and was negative. Long-term follow-up and vigilance for recurrence is warranted in patients like ours. Fewer than 20 cases of B-cell lymphoma involving the eyelids have been reported. To our knowledge, this is the first case of DLBCL of the eyelid that demonstrated spontaneous regression following cessation of immunosuppressive therapy. This case also highlighted the fact that in cases of recurrent chalazia—in addition to sebaceous carcinoma—lymphomatous infiltration should also be included in the differential diagnosis, especially in the setting of immunosuppression.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Ophthalmology, University of California, San Francisco, School of Medicine.
1. Starkebaum G. Rheumatoid arthritis, methotrexate, and lymphoma: risk substitution, or cat and mouse with Epstein-Barr virus? J Rheumatol. 2001;28(12):2573-2575.
Corresponding Author: Qi N. Cui, MD, PhD, Department of Ophthalmology, University of California, San Francisco, School of Medicine, 10 Koret St, K304 San Francisco, CA 94143-0730 ([email protected]). Conflict of Interest Disclosures: None reported. Funding/Support: This work was made possible in part by National Institutes of Health–National Eye Institute EY002162 Core Grant for Vision Research and by a Research to Prevent Blindness unrestricted grant. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
1146
Epstein-Barr virus has also been implicated in lymphoma occurring in patients with RA treated with long-term methotrexate therapy. Waldman and Callen4 reviewed 13 cases of lymphoma associated with methotrexate and found that 9 patients were EBV positive. In this subgroup, 8 of 9 cases demonstrated complete resolution following methotrexate discontinuation. Following methotrexate withdrawal, spontaneous tumor regression has been reported in up to 59% of patients with methotrexate-associated lymphomas, with complete remission generally occurring within 4 weeks.10 Owing to the high rate of spontaneous regression, rheumatologists and oncologists often observe methotrexateassociated lymphoproliferative lesions following cessation of immunosuppression rather than immediately starting chemotherapy and external beam radiotherapy. An observation period of up to 2 months following cessation of methotrexate before initiating lymphoma treatment has been advocated.
2. Georgescu L, Paget SA. Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf. 1999;20(6): 475-487. 3. van de Rijn M, Cleary ML, Variakojis D, Warnke RA, Chang PP, Kamel OW. Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis. Arthritis Rheum. 1996;39(4): 638-642. 4. Waldman MA, Callen JP. Self-resolution of Epstein-Barr virus-associated B-cell lymphoma in a patient with dermatomyositis following withdrawal of mycophenolate mofetil and methotrexate. J Am Acad Dermatol. 2004;51(2)(suppl):s124-s130. 5. Salloum E, Cooper DL, Howe G, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol. 1996;14(6):1943-1949.
6. Rasmussen PK, Ralfkiaer E, Prause JU, et al. Diffuse large B-cell lymphoma of the ocular adnexal region: a nation-based study. Acta Ophthalmol. 2013;91(2):163-169. 7. Knowles DM, Jakobiec FA, McNally L, Burke JS. Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987. Hum Pathol. 1990;21(9):959-973. 8. Meunier J, Lumbroso-Le Rouic L, Vincent-Salomon A, et al. Ophthalmologic and intraocular non-Hodgkin’s lymphoma: a large single centre study of initial characteristics, natural history, and prognostic factors. Hematol Oncol. 2004;22(4):143-158. 9. Knowles DM. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol. 1999;12 (2):200-217. 10. Ichikawa A, Arakawa F, Kiyasu J, et al. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 2013;91(1):20-28.
JAMA Ophthalmology September 2014 Volume 132, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
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