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BJO Online First, published on December 4, 2013 as 10.1136/bjophthalmol-2013-304309 Editorial
Can conjunctival lymphoma be a clinical diagnosis? Sarah Coupland,1 Steffen Heegaard2,3
Conjunctiva contains specialised lymphoid tissue and is a part of the mucosa-associated lymphoid tissue (MALT) system acting as a barrier to both endoantigens and exoantigens. Reactive lymphoid hyperplasia (RLH) is a result of antigen stimulation of the conjunctival MALT system. RLH affects males and females equally, and tends to occur in young patients.1 It has morphological, immunohistochemical and molecular genetic features, which indicate that the lesion consists of polyclonal B-lymphocytes and T-lymphocytes in similar proportions. On the other hand, non-Hodgkin lymphomas (NHL) of B-cell type can also arise within this conjunctival MALT system. Between one-third and one quarter of all ocular adnexal lymphoma are located in the conjunctiva.2 3 Conjunctival lymphoma consists of mainly four subtypes of B-NHL. The two low-grade malignant neoplasias are extranodal marginal B-cell lymphoma (EMZL) and follicular lymphoma, while the two high-grade B-NHLs are diffuse large B-cell lymphoma and mantle cell lymphoma. EMZL constitutes about one half of the conjunctival B-NHL.1 EMZL typically arises in conditions of chronic antigenic stimulation, as evidenced by the association of Helicobacter pylori, Campylobacter jejuni, Borrelia burgdorferi and hepatitis C virus with EMZLs that arise in the stomach, small intestine, skin and spleen, respectively.4 Of note, when EMZL is diagnosed at an early stage, removal of the antigenic stimulus may result in complete regression on the lymphoproliferation. The significance of Chlamydia psittaci with respect to the EMZL of the ocular adnexa remains unclear: there appears to be
substantial geographic variation in its association.5 A relationship between autoantigens, present in autoimmune diseases, and ocular adnexal EMZL seems likely as evidenced by somatic mutation analyses of these tumours, which suggest an antigen selection process.6–8 Recent evidence suggests that alterations of the A20 gene, located on chromosome 6, are involved in the pathogenesis of conjunctival EMZL,9 particularly those EMZL without any evident chromosomal translocations. Further, these alterations of A20 are of clinical relevance in that complete A20 inactivation is associated with poor lymphoma-free survival, and the patients with A20 mutation/deletion required significantly higher radiation dosages than those without the A20 abnormalities to achieve complete remission.10 Treatment of localised conjunctival EMZL is usually low-dose external radiotherapy, but other options include excision only, excision and topical chemotherapy, as well as intralesional chemotherapy.3 The clinical appearance of both conjunctival RLH and B-NHL is normally a ‘salmon patch’-like conjunctival swelling, without specific clinical signs that can aid differentiation between the two lesions (figure 1). The classical clinical signs of malignancy (eg, growth, ulceration, invasion of surrounding tissue, feeder vessels,
regional spread with lymph node enlargement) are features supporting the clinical diagnosis of lymphoma. However, while these features may be apparent in highgrade malignant lymphomas (eg, diffuse large B-cell lymphoma), they are usually not present in the indolent conjunctival EMZL. Therefore, a tissue biopsy should always be considered when a conjunctival lymphoid tumour presents (figure 2). The general rule should therefore be that these cases, even in children and young adults, should be suspected to be a lymphoma until proven otherwise. Should a conjunctival lymphoma be diagnosed, a full clinical work-up should be performed. This is very important since up to one-third of the patients have either regional lymph node involvement and/or systemic involvement at the time of diagnosis without having symptoms.1 11 Therefore, (even) the ophthalmologist must probe the medical history of the patient regarding B-symptoms (ie, night sweat, fever and weight loss). Clinical staging of the ocular adnexal lymphomas can be performed using the conventional Ann Arbor Staging system12 and/or with the TNM-AJCC-based system, which was recently developed13 and has been assessed by some centres.14 15 Beykin et al present a series of 11 young patients with the common complaint of a ‘salmon patch’ swelling of the conjunctiva.16 Their aim was to compare the clinical diagnosis with the histopathological diagnosis, which also included extensive immunohistochemical and molecular pathology ‘work-up’ using IgH-PCR. The article is of interest since there are limited reports in the literature concerning these lesions in young patients
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Pathology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark; 3Department of Neuroscience and Pharmacology, Eye Pathology Institute, University of Copenhagen, Copenhagen, Denmark Correspondence to Professor Sarah Coupland, Pathology, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK;
[email protected]
Figure 1 Caruncular swelling with ectasia of the overlying blood vessels and compression of the adjacent bulbar conjunctiva. This lesion has grown rapidly, but it was unclear clinically whether this represented a benign or malignant lesion.
Coupland S, et al. BrArticle J Ophthalmol Month (or 2013 their Vol 0 Noemployer) 0 Copyright author
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Figure 2 Histological examination of the lesion demonstrated that it consisted of a monomorphic infiltrate of small atypical cells. On further immunohistochemical examination, these cells were neoplastic B-lymphocytes that demonstrated aberrant immunophenotypes, confirming the diagnosis of B-non-Hodgkin lymphomas (HE stain, ×60 objective).
and adolescents. Further, the study highlights the discrepancies that may arise between morphological and clonality results, and the care that has to be applied when interpreting all molecular genetic results. For example, the authors found rearranged (ie, clonal) IgH genes in 1/7 cases of RLH and in one out of two cases of EMZL.16 Should the morphology and immunohistology of a suspected B-NHL be equivocal, molecular analysis in the form of IgH-PCR and IgΚ-PCR should be performed. The inclusion of the latter, that is, the light chain PCR, increases the accuracy of the test.17 This is particularly in the case of follicular lymphomas, in which the primer binding sites for IgH-PCR can be highly mutated. However, there will always be cases of lymphoproliferative lesions that remain unclear. Therefore, close collaboration between the ophthalmologist and the pathologist is essential, to collect all relevant data of each patient, in order to achieve the correct (or most likely) diagnosis.16 In their article, the authors suggest the use of topical antiallergic eye drops in the age group less than 22 years before taking a biopsy. This could be considered an acceptable approach but must be performed under close clinical surveillance with strict photographic documentation by the same experienced ocular oncology
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team, as the possibility always remains that these lesions could be B-NHL. In conclusion, a conjunctival lymphoma should be suspected in a case of ‘salmon patch’-like lesions until proven otherwise, even in children or young adults, and a full systemic clinical work-up is recommended if the diagnosis is verified.
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Contributors All the authors made a (1) substantial contributions to conception and design; (2) drafting the article or revising it critically for important intellectual content and (3) final approval of the version to be published.
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Competing interests None.
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Patient consent Obtained. Ethics approval The IRB Copenhagen University, Denmark.
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Provenance and peer review Commissioned; internally peer reviewed.
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To cite Coupland S, Heegaard S. Br J Ophthalmol Published Online First: [please include Day Month Year] doi:10.1136/bjophthalmol-2013-304309
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▸ http://dx.doi.org/10.1136/bjophthalmol-2013303527 Br J Ophthalmol 2013;0:1–2. doi:10.1136/bjophthalmol-2013-304309
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Coupland S, et al. Br J Ophthalmol Month 2013 Vol 0 No 0
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Can conjunctival lymphoma be a clinical diagnosis? Sarah Coupland and Steffen Heegaard Br J Ophthalmol published online December 4, 2013
doi: 10.1136/bjophthalmol-2013-304309
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