Can conjunctival lymphoma be aclinical diagnosis?Sarah Coupland,1 Steffen Heegaard2,3

Conjunctiva contains specialised lymphoidtissue and is a part of the mucosa-associatedlymphoid tissue (MALT) system acting as abarrier to both endoantigens and exoanti-gens. Reactive lymphoid hyperplasia (RLH)is a result of antigen stimulation of the con-junctival MALT system. RLH affects malesand females equally, and tends to occur inyoung patients.1 It has morphological,immunohistochemical and moleculargenetic features, which indicate that thelesion consists of polyclonal B-lymphocytesand T-lymphocytes in similar proportions.

On the other hand, non-Hodgkin lymph-omas (NHL) of B-cell type can also arisewithin this conjunctival MALT system.Between one-third and one quarter of allocular adnexal lymphoma are located in theconjunctiva.2 3 Conjunctival lymphomaconsists of mainly four subtypes of B-NHL.The two low-grade malignant neoplasiasare extranodal marginal B-cell lymphoma(EMZL) and follicular lymphoma, whilethe two high-grade B-NHLs are diffuselarge B-cell lymphoma and mantle celllymphoma. EMZL constitutes about onehalf of the conjunctival B-NHL.1

EMZL typically arises in conditions ofchronic antigenic stimulation, as evi-denced by the association of Helicobacterpylori, Campylobacter jejuni, Borreliaburgdorferi and hepatitis C virus withEMZLs that arise in the stomach, smallintestine, skin and spleen, respectively.4

Of note, when EMZL is diagnosed at anearly stage, removal of the antigenicstimulus may result in complete regressionon the lymphoproliferation. The signifi-cance of Chlamydia psittaci with respectto the EMZL of the ocular adnexaremains unclear: there appears to be

substantial geographic variation in itsassociation.5 A relationship between auto-antigens, present in autoimmune diseases,and ocular adnexal EMZL seems likely asevidenced by somatic mutation analyses ofthese tumours, which suggest an antigenselection process.6–8 Recent evidence sug-gests that alterations of the A20 gene,located on chromosome 6, are involved inthe pathogenesis of conjunctival EMZL,9

particularly those EMZL without anyevident chromosomal translocations.Further, these alterations of A20 are ofclinical relevance in that complete A20inactivation is associated with poorlymphoma-free survival, and the patientswith A20 mutation/deletion required sig-nificantly higher radiation dosages thanthose without the A20 abnormalities toachieve complete remission.10 Treatmentof localised conjunctival EMZL is usuallylow-dose external radiotherapy, but otheroptions include excision only, excisionand topical chemotherapy, as well as intra-lesional chemotherapy.3

The clinical appearance of both con-junctival RLH and B-NHL is normally a‘salmon patch’-like conjunctival swelling,without specific clinical signs that can aiddifferentiation between the two lesions(figure 1). The classical clinical signs ofmalignancy (eg, growth, ulceration, inva-sion of surrounding tissue, feeder vessels,

regional spread with lymph node enlarge-ment) are features supporting the clinicaldiagnosis of lymphoma. However, whilethese features may be apparent in high-grade malignant lymphomas (eg, diffuselarge B-cell lymphoma), they are usuallynot present in the indolent conjunctivalEMZL. Therefore, a tissue biopsy shouldalways be considered when a conjunctivallymphoid tumour presents (figure 2). Thegeneral rule should therefore be that thesecases, even in children and young adults,should be suspected to be a lymphomauntil proven otherwise.

Should a conjunctival lymphoma bediagnosed, a full clinical work-up shouldbe performed. This is very importantsince up to one-third of the patients haveeither regional lymph node involvementand/or systemic involvement at the timeof diagnosis without having symptoms.1 11

Therefore, (even) the ophthalmologistmust probe the medical history of thepatient regarding B-symptoms (ie, nightsweat, fever and weight loss). Clinicalstaging of the ocular adnexal lymphomascan be performed using the conventionalAnn Arbor Staging system12 and/or withthe TNM-AJCC-based system, which wasrecently developed13 and has beenassessed by some centres.14 15

Beykin et al present a series of 11young patients with the common com-plaint of a ‘salmon patch’ swelling of theconjunctiva.16 Their aim was to comparethe clinical diagnosis with the histopatho-logical diagnosis, which also includedextensive immunohistochemical andmolecular pathology ‘work-up’ usingIgH-PCR. The article is of interest sincethere are limited reports in the literatureconcerning these lesions in young patients

Figure 1 Caruncular swelling with ectasia of the overlying blood vessels and compression ofthe adjacent bulbar conjunctiva. This lesion has grown rapidly, but it was unclear clinicallywhether this represented a benign or malignant lesion.

1Pathology, Department of Molecular and ClinicalCancer Medicine, Institute of Translational Medicine,University of Liverpool, Liverpool, UK; 2Department ofOphthalmology, Glostrup Hospital, University ofCopenhagen, Copenhagen, Denmark; 3Department ofNeuroscience and Pharmacology, Eye PathologyInstitute, University of Copenhagen, Copenhagen,Denmark

Correspondence to Professor Sarah Coupland,Pathology, Department of Molecular and ClinicalCancer Medicine, Institute of Translational Medicine,University of Liverpool, Daulby Street, Liverpool L693GA, UK;s.e.coupland@liverpool.ac.uk

574 Coupland S, et al. Br J Ophthalmol May 2014 Vol 98 No 5

Editorial

group.bmj.com on October 5, 2014 - Published by bjo.bmj.comDownloaded from

and adolescents. Further, the study high-lights the discrepancies that may arisebetween morphological and clonalityresults, and the care that has to be appliedwhen interpreting all molecular geneticresults.

For example, the authors found rear-ranged (ie, clonal) IgH genes in 1/7 casesof RLH and in one out of two cases ofEMZL.16 Should the morphology andimmunohistology of a suspected B-NHLbe equivocal, molecular analysis in theform of IgH-PCR and IgΚ-PCR should beperformed. The inclusion of the latter,that is, the light chain PCR, increases theaccuracy of the test.17 This is particularlyin the case of follicular lymphomas, inwhich the primer binding sites forIgH-PCR can be highly mutated.However, there will always be cases oflymphoproliferative lesions that remainunclear. Therefore, close collaborationbetween the ophthalmologist and thepathologist is essential, to collect all rele-vant data of each patient, in order toachieve the correct (or most likely)diagnosis.16

In their article, the authors suggest theuse of topical antiallergic eye drops in theage group less than 22 years before takinga biopsy. This could be considered anacceptable approach but must be per-formed under close clinical surveillancewith strict photographic documentationby the same experienced ocular oncology

team, as the possibility always remainsthat these lesions could be B-NHL.In conclusion, a conjunctival lymphoma

should be suspected in a case of ‘salmonpatch’-like lesions until proven otherwise,even in children or young adults, and afull systemic clinical work-up is recom-mended if the diagnosis is verified.

Contributors All the authors made a (1) substantialcontributions to conception and design; (2) drafting thearticle or revising it critically for important intellectualcontent and (3) final approval of the version to bepublished.

Competing interests None.

Patient consent Obtained.

Ethics approval The IRB Copenhagen University,Denmark.

Provenance and peer review Commissioned;internally peer reviewed.

To cite Coupland S, Heegaard S. Br J Ophthalmol2014;98:574–575.

Published Online First 4 December 2013

▸ http://dx.doi.org/10.1136/bjophthalmol-2013-303527

Br J Ophthalmol 2014;98:574–575.doi:10.1136/bjophthalmol-2013-304309

REFERENCES1 Coupland SE, Krause L, Delecluse H-J, et al.

Lymphoproliferative lesions of the orbit and ocularadnexa: analysis of 112 cases. Ophthalmology1998;105:1430–41.

2 Coupland SE, Hellmich M, Auw-Haedrich C, et al.Prognostic value of cell-cycle markers in ocular adnexallymphoma: an assessment of 230 cases. Graefe’s ArchClin Exp Ophthalmol 2004;242:130–45.

3 Sjö LD. Ophthalmic lymphoma: epidemiology andpathogenesis. Acta Ophthalmol 2009;87(Thesis 1):1–20.

4 Isaacson PG, MQ Du. MALT lymphoma: frommorphology to molecules. Nat Rev Cancer2004;4:644–53.

5 Chanudet E, Zhou Y, Bacon CM, et al. Chlamydiapsittaci is variably associated with ocular adnexalMALT lymphoma in different geographical regions.J Pathol 2006;209:344–51.

6 Coupland SE, Foss HD, Anagnostopoulos I, et al.Immunoglobulin VH gene expression amongextranodal marginal zone B-cell lymphomas of theocular adnexa. Invest Ophthalmol Vis Sci1999;40:555–62.

7 Hara Y, Nakamura N, Kuze T, et al. Immunoglobulinheavy chain gene analysis of ocular adnexalextranodal marginal zone B-cell lymphoma. InvestOphthalmol Vis Sci 2000;42:2450–7.

8 Bahler DW, Szankasi P, Kulkarni S, et al. Use ofsimilar immunoglobulin VH gene segments by MALTlymphomas of the ocular adnexa. Mod Pathol2009;22:833–8.

9 Chanudet E, Huang Y, Ichimura K, et al. A20 istargeted by promoter methylation, deletion andinactivating mutation in MALT lymphoma. Leukemia2010;24:483–7.

10 Bi Y, Zeng N, Chanudet E, et al. A20 inactivation inocular adnexal MALT lymphoma. Haematologica2012;97:926–30.

11 Sjö LD, Heegaard S, Prause JU, et al. Extranodalmarginal zone lymphoma in the ocular region:clinical, immunophenotypical, and cytogeneticalcharacteristics. Invest Ophthalmol Vis Sci2009;50:516–22.

12 Carbone PP, Kaplan HS, Musshoff K, et al.Report of the Committee on Hodgkin’s diseasestaging classification. Cancer Res 1971;31:1860–1.

13 Coupland SE, White VA, Rootman J, et al. ATNM-based staging system for ocular adnexallymphomas. Arch Path Lab Med 2009;133:1262–7.

14 Lee SE, Paik JS, Cho WK, et al. Feasibility of theTNM-based staging system of ocular adnexalextranodal marginal zone lymphoma ofmucosa-associated lymphoid tissue (MALTlymphoma). Am J Hematol 2011;86:262–6.

15 Aronow ME, Portell CA, Rybicki LA, et al. Ocularadnexal lymphoma: assessment of atumor-node-metastasis staging system.Ophthalmology 2013;120:1915–19.

16 Beykin G, Pe’er J, Amir G, et al. Pediatric andadolescent elevated conjunctival lesions in the plicalarea-lymphoma or reactive lymphoid hyperplasia?Br J Ophthalmol 2014;98:645–50.

17 Liu H, Bench AJ, Bacon CM, et al. A practicalstrategy for the routine use of BIOMED-2 PCRassays for detection of B- and T-cell clonality indiagnostic haematopathology. Br J Haematol2007;138:31–43.

Figure 2 Histological examination of the lesion demonstrated that it consisted of amonomorphic 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).

Coupland S, et al. Br J Ophthalmol May 2014 Vol 98 No 5 575

Editorial

group.bmj.com on October 5, 2014 - Published by bjo.bmj.comDownloaded from

doi: 10.1136/bjophthalmol-2013-304309December 4, 2013

2014 98: 574-575 originally published onlineBr J Ophthalmol Sarah Coupland and Steffen Heegaard diagnosis?Can conjunctival lymphoma be a clinical

http://bjo.bmj.com/content/98/5/574.full.htmlUpdated information and services can be found at:

These include:

References http://bjo.bmj.com/content/98/5/574.full.html#ref-list-1

This article cites 16 articles, 4 of which can be accessed free at:

serviceEmail alerting

the box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up in

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.com on October 5, 2014 - Published by bjo.bmj.comDownloaded from