conjunctival lymphangiectasia: a report of 11 cases and review of literature

SURVEY OF OPHTHALMOLOGY VOLUME 57 � NUMBER 2 � MARCH–APRIL 2012

CLINICAL PATHOLOGIC REVIEWSSTEFAN SEREGARD AND MILTON BONIUK, EDITORS

Conjunctival Lymphangiectasia: A Report of 11 Casesand Review of LiteratureJames Welch, BSc, MRCOphth,1 Sathish Srinivasan, FRCS(Ed), FRCOphth,1,2

Douglas Lyall, MRCOphth,1 and Fiona Roberts, MD, FRCPath3

1Department of Ophthalmology, Ayr Hospital, Ayrshire and Arran National Health Service, Ayrshire, Scotland, UnitedKingdom; 2Faculty of Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom; and 3Department ofPathology, Western Infirmary, Glasgow, Scotland, United Kingdom

� 2012 byAll rights

Abstract. Conjunctival lymphangiectasia is an uncommon clinical condition in which there isdilatation of lymphatic channels in the bulbar conjunctiva. Conjunctival lymphangiectasia is a rarelyappreciated ocular surface disorder that typically occurs as a secondary phenomenon in response tolocal lymphatic scarring or distal obstruction. Conjunctival lymphangiectasia can either be unilateral orbilateral with focal or diffuse bulbar chemosis. We present 11 cases of biopsy-proven conjunctivallymphangiectasia. Of the 11 cases, 3 presented with bilateral diffuse bulbar chemosis, 1 had diffuseunilateral chemosis, and the remaining 7 presented with focal (!90�) bulbar chemosis. Three of thesecases had co-existing pterygium, and one case presented with focal bulbar chemosis and a conjunctivalkeratin horn. All underwent surgical excision of the involved conjunctiva, either with no graft (n 5 6),combined with amniotic membrane transplant (n 5 3), or combined with conjunctival autograft(n 5 2). (Surv Ophthalmol 57:136--148, 2012. � 2012 Elsevier Inc. All rights reserved.)

Key words. conjunctiva � lymphangiectasia � lymphatic vessels � chemosis � conjunctivalcyst � surgical excision � amniotic membrane transplant � conjunctival autograft

Conjunctival lymphangiectasia is a rare condition inwhich the normal lymphatic vessels are dilated andprominent within the bulbar conjunctiva.20 It occursin two forms: a diffuse enlargement of lymphatics thatappears clinically as chemosis or focal dilated lym-phatics thatmanifest as a cyst or a series of cysts (‘‘stringofpearls’’).47Onclinical biomicroscopic examination,lymphangiectasiaappears as channels containingclearfluid separated by diaphanous septate walls. In 1880Leber used the term ‘‘Lymphangiectasia haemorrhag-ica conjunctivae’’ to describe a condition where theconjunctival lymphatics were filled with blood as the

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result of abnormal connections between conjunctivallymphatic and the conjunctival vascular system.55 Wereport a seriesof 11casesofbiopsy-provenconjunctivallymphangiectasia, discuss the distinctive histologicalcharacteristics of this condition, and review theliterature on conjunctival lymphangiectasia and itsdifferential diagnoses.

Patients and Methods

We reviewed the computerized flies at the re-gional Ocular Pathology Laboratory based at the

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CONJUNCTIVAL LYMPHANGIECTASIA 137

Western Infirmary, Glasgow, Scotland, betweenJanuary 1995 and December 2010. We identifiedand reviewed 11 cases with the diagnosis ofconjunctival lymphangiectasia. We compared ourfindings with those reported in the literature.

Results

The patient characteristics are summarized inTable 1.

Illustrative Patient Reports

PATIENT 1

A 59-year-old woman presented with a one-yearhistory of ocular irritation associated with persistentbilateral conjunctival swelling. This immediatelyfollowed an upper respiratory tract infection withassociated conjunctivitis and was presumed to be ofviral etiology. She had been treated with topicallubricants and corticosteroids with little benefit.Visual acuity was 20/20 in each eye. Slit lampbiomicroscopy revealed diffuse chemosis affectingthe inferotemporal conjunctiva (Figs. 1, 2). Anteriorsegment ocular coherence tomography was used tofurther delineate the abnormality (Fig. 3). A clinicaldiagnosis of conjunctival lymphangiectasia wassuspected. Magnetic resonance imaging (MRI) ofthe orbits and head and neck were normal. Thyroidfunction tests, blood count, and serum biochemistrywere normal. Excisional biopsy of the chemoticconjunctiva with amniotic membrane and fibringlue was performed on each eye separated by an 8-week interval. Histologically both specimens dem-onstrated lymphangiectasia within the submucosaand squamous metaplasia of the surface epithelium.She remained asymptomatic during 12 months offollow-up with no evidence of recurrence.

PATIENT 2

A 53-year-old man presented with a 6-monthhistory of ocular irritation and swelling OD. Fiveyears before he had undergone primary nasalpterygium excision of the right eye with noconjunctival graft . Best corrected visual acuitieswere 20/20 in both eyes. The left eye was normal.Examination of the right eye revealed a cystic arealocated temporally within the bulbar conjunctivaand extending three clock hours. The clinicalsuspicion was conjunctival lymphangiectasia. MRIof the orbits and head and neck were normal.Thyroid function tests and serum biochemistry werewithin normal limits. Following informed consenthe underwent excisional biopsy of the involved

conjunctiva with fibrin-glue--assisted amniotic mem-brane transplantation. Histologically the excisedconjunctiva showed numerous dilated lymphaticswithin the submucosa and squamous metaplasia ofthe surface epithelium. Two months followingsurgery, localized cystic chemosis developed tempo-ral to the excised area. He has remained asymptom-atic during 8 months of follow-up.

PATIENT 3

A 49-year-old man had a 2-year history of in-termittent nasal bulbar redness and irritation in theleft eye. He had been treated with topical cortico-steroids during these episodes. Visual acuity was20/20 in both eyes. The right eye was normal. Slitlamp biomicroscopy of the left eye revealed an areaof thickened conjunctiva with cystic elements in thetemporal bulbar conjunctiva that encroached ontothe cornea in a wing-like fashion. Based on theclinical appearance a diagnosis of primary cysticpterygium was reached. He underwent excision ofthe pterygium with fibrin-glue--assisted conjunctivalautograft. No sutures were used to secure theautograft. Histologically the specimen showed typi-cal elastotic degeneration, with areas of lymphan-giectasia within the submucosa. The patient hasremained asymptomatic during 6 months of follow-up with no evidence of pterygium recurrence orchemosis.

PATIENT 4

A 48-year-old man had a 6-year history of in-termittent nasal bulbar redness and irritation in theleft eye. He used topical lubrications for symptom-atic relief. Visual acuity was 20/20 in both eyes. Theright eye was normal. Slit lamp biomicroscopy of theleft eye revealed an extensive area of thickenedconjunctiva that encroached onto the nasal cornea;a clinical diagnosis of primary pterygium wasreached. Excision of the pterygium with fibrin-glue--assisted conjunctival autograft was performed.No sutures were used to secure the autograft.Histologically the specimen showed typical elastoticdegeneration, with areas of lymphangiectasia withinthe submucosa (Fig. 4). The patient has remainedasymptomatic during 8 months of follow-up with noevidence of pterygium recurrence or chemosiswithin the bulbar conjunctiva.

PATIENT 5

A 47-year-old woman had a 2-year history ofrecurrent irritation and swelling on the outer aspectof her right eye. She wore monthly disposablesilicone hydrogel contact lenses. Best correctedvisual acuity was 20/20 in both eyes. Slit lamp

TABLE 1

Patient Characteristics

CaseAge

(years) SexDate of

PresentationPresentingSymptoms Co-morbidity Clinical Signs

ClinicalDiagnosis

HistopathologicalDiagnosis Treatment Outcome

1 59 F Jun 2010 Irritation Preceding viralconjunctivitis

Bilateralinferotemporal(!180 �) diffusechemosis

Lymphangectasia Lymphangectasiawith epithelialsquamousmetaplasia

Bilateralexcisionwith AMT

No recurrence

2 53 M Sep 2010 Irritation Ipsilateralpterygiumexcision 2005

Focal temporal(!90 �)unilateralchemosis

Lymphangectasia Lymphangectasiawith epithelialsquamousmetaplasia

Excisionwith AMT

Partialrecurrence

3 49 M Sep 2010 Irritation Primarypterygium

Focal nasal(!90 �)unilateralchemosis

Primary pterygiumwith cysticcomponent

Lymphangectasiawith epithelialsquamousmetaplasia

Excision withconj autograft

No recurrence

4 48 M Oct 2010 Irritation Primarypterygium

Focal nasal(!90 �)unilateralchemosis

Primary pterygiumwith cysticcomponent

Lymphangectasiawith epithelialsquamousmetaplasia


No recurrence

5 47 F Oct 2010 IrritationRecurrentepibulbarswelling

Nil Focal temporal(!90 �)conjunctivalthickening withkeratinisation

Conjunctivalkeratin horn

Lymphangectasiawith squamousmetaplasia ofepithelium andkeratinization

Direct excision No recurrence

6 65 M Feb 2010 Epibulbarswelling

Nil Focal temporal(!90 �)unilateralchemosis

Superficiallymphangioma

Lymphangectasia Directexcision

Partialrecurrence

7 33 F Dec 2010 Irritation Primarypterygium

Focal temporal(!90 �)unilateralchemosis

Primarypterygiumwith cysticcomponent

Lymphangectasiawith epitheialsquamousmetaplasia


No recurrence

8 68 M Dec 1995 Irritation GlaucomaBlepharitis

Bilateral diffusechemosis

Allergic/toxicconjunctivitis


Recurrence

9 70 M Jun 2008 Irritation Ipsilateralsenileectropion

Diffuse unilateralchemosis

Not recorded Lymphangectasia Directexcision

Partialrecurrence

10 59 M Aug 2008 Irritation Nil Diffuse bilateralchemosis

Allergicconjunctivitis


Recurrence

11 44 F Oct 2008 Irritation Nil Focal temporal(!90 �)unilateralchemosis

Inclusion cyst Lymphangectasia Directexcision

Partialrecurrence

AMT 5 amniotic membrane transplantation; conj 5 conjunctival.

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Fig. 1. A: Slit lamp photograph of Patient 1, showing localized conjunctival swelling in the inferotemporal aspect of thebulbar conjunctiva in left eye (OS) (arrows). B: Slit lamp photograph of the same case, with fluorescein staininghighlighting the area of bulbar conjunctival swelling in the OS.


biomicroscopy revealed localized cystic swellinginvolving the temporal bulbar conjunctiva of theright eye with an overlying keratin horn (Figs. 5A, 5B).She underwent excision biopsy of the lesion undertopical anesthesia. On histological examination theexcised conjunctiva showedmarked lymphangiectasiawithin the submucosa and squamous metaplasia andkeratinisation of the surface epithelium (Figs. 5C,5D). The patient has remained asymptomatic during 8months of follow-up with no evidence of recurrence.

PATIENT 6

A 65-year-old man gave a 6-month history ofswelling on the outer aspect of his left eye. He wastreated with topical lubricants with limited effect.Visual acuity was 20/20 in both eyes. Examination ofthe right eye was normal. The left eye showeda localized area of superotemporal cystic chemosisof the bulbar conjunctiva in a classic ‘‘string of pearls’’appearance (Fig. 6). Excisional biopsy of the involvedconjunctiva was performed. Histological examina-tion of the specimen showed lymphangiectasiawithin the submucosa and squamous metaplasia of

Fig. 2. A: Slit lamp photograph of Patient 1, showing localizebulbar conjunctiva in the right eye (OD) (arrow). B: Slit lampthe area of bulbar conjunctival swelling in the OD.

the surface epithelium. The patient has remainedasymptomatic during one year of follow-up despitede novo localized cystic chemosis temporal to theexcised area.

PATIENT 7

A 33-year-old woman presented with a 1-yearhistory of persistent irritation and redness of theinner aspect of the right eye. She used topicallubrications for symptomatic relief. Visual acuity was20/20 in both eyes. Slit lamp biomicroscopyrevealed a primary nasal pterygium encroaching 2mm onto the cornea. There was no associatedchemosis. As she was symptomatic, she underwentpterygium excision with fibrin-glue--assisted con-junctival autograft. No sutures were used to securethe autograft. Histological examination of thespecimen confirmed a pterygium with elastoticdegeneration within the submucosa and squamousmetaplasia of the surface epithelium (Fig. 7). Therewas accompanying lymphangiectasia. The patienthas remained asymptomatic during 5 months of

d conjunctival swelling in the inferotemporal aspect of thephotograph of the same case, with slit beam highlighting

Fig. 3. Enhanced high resolution anterior segmentocular coherence tomography scan picture demonstratingthe cystic spaces within the conjunctiva in the OS ofPatient 1.

140 Surv Ophthalmol 57 (2) March--April 2012 WELCH ET AL

follow-up with no evidence of pterygium recurrenceor chemosis.

Histological Features

The lymphatic channels of the conjunctivacontain valves that allow for directed drainagetowards the inner and outer canthi. Obstructioncan occur in inflammatory and neoplastic disease.This obstruction leads to lymphangiectasia or, ifextreme, lymphatic cysts. Excised tissue will showdilated channels lined by a flattened endothelium.The ultrastructural characteristics of ectatic lym-phatic vessels do not differ significantly froma normal lymphatic vessel. The vessel is, however,dilated, and the surrounding lamina propria is oftenedematous, presumably because these dilated ves-sels leak. The channels may contain proteinaceousfluid or clusters of lymphocytes (Fig. 8A). This maybe accompanied by squamous metaplasia andkeratinisation of the overlying surface epithelium(Fig. 8B) as part of a reactive process related to localtrauma. If necessary, dilated lymphatic channels canbe differentiated from capillaries by immunohisto-chemical staining for D2-40, a sensitive and specificmarker of lymphatic endothelium (Fig. 8C).29 Thesurrounding lamina propria may contain scattered

Fig. 4. A: Low-power view of pterygium associated with lymphdegeneration towards the right (arrow). The cluster of dilate(hematoxylin and eosin; magnification �20). B: High powerinflammation overlying the dilated vessels (star) (hematoxylin

inflammatory cells or show fibroblastic proliferationor scarring, supporting the secondary nature of thisprocess.

Discussion

The human lymphatic system, first described in1627 by Gasper Aselli,30 functions to remove excessinterstitial fluid and macromolecules from theextracellular space and transports this fluid throughlymph nodes before returning it to the venouscirculation.19 Despite its integral role in preservingtissue fluid homeostasis, the study of lymphaticsremains at a rudimentary level when compared toblood vessels.101

Conjunctival interstitial tissue fluid entersthrough the initial lymphatic (blind-ended tubesthat are made up of endothelial cells) locatedimmediately under the epithelium. The cells aretethered to surrounding stroma by anchoringfilaments that prevent the tubes from collapsing.14

The precise mechanism that drives fluid into theseinitial lymphatics has not yet been fully eluci-dated.102 We do know, however, that lymphatic flowis created by the development of fluid pressuregradients between the initial lymphatic and down-stream collector channels.69,102 Unidirectional lu-minal valves are present throughout the lymphaticsystem and prevent backflow,22 but these valves maynot be completely effective, as Shields et al reporteda case of retrograde metastasis of a preauricularcutaneous melanoma to the ipsilateral conjunctivallymphatics.83

It was once thought that the conjunctivae werethe only components of the globe and orbit tohave a lymphatic drainage system; however,lymphatic tissue has been consistently found inthe lacrimal gland and optic nerve in humans andin the orbital apex and extraocular muscles in

angiectasia. There is a purplish area representing elastoticd lymphatics is seen towards the left of the picture (star)showing area of lymphangiectasia. There is some chronicand eosin; magnification �40).

Fig. 5. A: Slit lamp photograph of Patient 5 showing a localized conjunctival swelling in the inferotemporal aspect of theright eye with overlying cyst. B: High magnification slit lamp photograph of the same eye showing the keratin plug at theapex of the cyst. C: This patient presented with a keratin horn. Histology shows a large cystically dilated lymphaticchannel (L) with several smaller lymphatic channels in the adjacent tissues. Presumably due to protrusion of the cyst andlocal trauma there is squamous metaplasia and localised hyperkeratosis (arrows) of the overlying mucosa (hematoxylinand eosin; magnification �40). D: At higher power the cystically dilated lymphatic channel contains proteinaceous fluidand there are scattered smaller lymphatic channels (L) in the surrounding tissues. Inflammation (arrows) is also presentin the stroma (hematoxylin and eosin; magnification �100).


other primates.30,82 The distinguishing electronmicroscopic features of initial lymphatics thatpermit differentiation from vascular capillariesare well characterized.14,30,82 Both conjunctivaland corneal lymphatics have been identified usingin vivo confocal microscopy and show featuresmorphologically distinct from adjacent bloodvessels and discrepancies with respect to leukocyteflow velocities, yet some descriptions make noreference to bulbar conjunctival lymphaticsat all.21,67

Fig. 6. A: Slit lamp photograph of Patient 6 showing localizedof pearls’’ appearance involving the temporal bulbar conjunctomography scan of the same eye showing multiple cystic spa

The organization of the conjunctival lymphaticshas been delineated using vital dyes and is dividedinto several groups.60,89,93 A pericorneal lymphaticring (lymphatic circle of Teichmann) forms a denseplexus of tiny lymphatic vessels along the limbusmeasuring about 1 mm in size. These then coalesceas they leave the limbus, forming a system of largerradially orientated vessels. At between 4 to 8 mmbehind the limbus, large collector channels runcircumferentially ( pericorneal lymphatic ring), andthese receive lymph from the radial lymph vessels.

, linear bulbar conjunctival swelling with the classic ‘‘stringtiva of the left eye. B: Anterior segment ocular coherenceces with the conjunctiva.

Fig. 7. A: This specimen was removed as a pterygium and shows focal eosinophilic pink material in the superficial stroma(arrows) and dilated lymphatic channels (L) deep to this (hematoxylin and eosin; magnification �40). B: Theeosinophilic material is confirmed as degenerate elastic fibers (E) (elastica van Gieson; magnification �20).


It is thought that there are connections between thedeep conjunctival venous plexus and the collectorchannels, and on occasion retrograde flow results inthe lymphatic channel filling with blood (lymphan-giectasia hemorrhagica). The collector channelsdrain into one or two trunks, and these draintowards the lateral and medial commissures, wherethey join the lymphatic outflow of the eyelids.36

Fig. 8. A: Conjunctival mucosa with numerous dilated lympcontrast to the capillaries (C). There is mild chronic inflammagnification �40). B: On higher power there is patchy squaand eosin; magnification �100). C: Immunohistochemical stai(arrows) (D2-40; magnification �200).

There are no conjunctival lymph nodes.93 Thesubsequent drainage of the eyelid lymphatics wasthought to be by two main groups of vessels. Amedial group of lymphatic vessels drains the medialupper and lower eyelids and terminates in theipsilateral submandibular lymph nodes; a lateralgroup of lymphatics drains the lateral ends of botheyelids and terminates in the ipsilateral superficial

hatic channels (L). These contain proteinaceous fluid inmation in the stroma (arrows) (hematoxylin and eosin;mous metaplasia of the surface epithelium (hematoxylinning for D2-40 confirming dilatation of lymphatic channels


parotid lymph nodes. With the development ofnewer mapping modalities—namely, 99mTechneti-um lymphoscintigraphy—there is an appreciation ofvariability in drainage patterns between individ-uals.72 The majority of lymphatic basins are locatedin the parotid and anterior cervical nodes.11,24

Recent advances in the field of molecular biologyhave permitted the identification of lymphatics fromother than purely histological criteria.2,49 This hasbeen driven by the appreciation of the importantrole that lymphatics play in tumor metastasis andinflammatory conditions such as transplant rejec-tion.1,39,51,104 Vascular endothelial growth factorreceptor 3 (VEGFR-3), through it two ligands,VEGF-C and VEGF-D, is considered the majorregulator of lymphangiogenesis.3,49,95 Other molec-ular markers specific for lymphatic vessels includelymphatic vessel endothelium hyaluronic acid re-ceptor and the novel monoclonal antibody D2-40.13,46

Genetic mapping of the autosomal dominantform of hereditary primary lymphedema (Milroydisease) has identified that the disease can beattributed to a point mutation that inactivatesVEGFR-3 signaling.40 A murine model for thisdisease has been developed which has been usedextensively to investigate the phenotypic conse-quences of deranged lymphangiogenesis.48 Primarylymphedema in humans, resulting in congenitalconjunctival lymphangiectasia, has also been re-ported in Klippel-Trenaunay-Weber and Turnersyndromes.8,75

Nevertheless, the vast majority of conjunctivallymphangiectasia cases seen in clinical practice arenot congenital. Rather, they represent a secondarylymphedema following disruption or obstruction oflymphatic pathways by other disease processes or asa consequence of surgery or radiotherapy. Patientsmay present because of cosmetic concerns or, morefrequently, local irritation from tear-film distur-bances provoked by epibulbar irregularity.

The history must specifically elicit whether thepatient is aware of a head or neck mass or has beentreated for such tumors previously. Harris et alreported a series of six such patients, and althoughno cases of tumor recurrence at the primary site,regional nodes, or orbital apex were identified.Persistent chemosis was thought to representsurgery- and radiation-induced obstruction of lym-phatic/venous outflow channels.36 Similarly, cos-metic blepharoplasties are a recognized precipitantof conjunctival lymphangiectasia.23,47,58,68 In situa-tions where conjunctival swelling is associated withhemorrhage, it is important to establish whether thisis recurrent and the time course over which theblood clears. Clearing is reported to occur in 2--4

days, but may take several weeks, revealing persis-tent, ectatic, sausage-like conjunctival lymphvessels.6,54,60,81

The history should identify medical conditionsresulting in systemic hypoproteinemia (nephroticsyndrome, malnutrition), local venous hypertension(thyroid eye disease, orbital apex syndrome, cavern-ous sinus thrombosis, carotid-cavernous fistula), andincreased vascular permeability (vasomotor instabil-ity, allergy), as all these can drive fluid into theinterstitial compartment resulting in chemosis.Travel to West and Central Africa is relevant, asLoa Loa infestation can appear as sausage-likedilations within the conjunctiva.5

Examination to identify any local masses orlymphadenopathy within the head and neck ismandatory, and computerized tomography or MRImay be required. The laterality and location of theconjunctival swelling is determined. Experiencesuggests that lymphangiectasia is most likely to belocated within the temporal conjunctiva or de-pendent when it is more extensive.47,60 Whereblood is present within these vessels, some mayexhibit a horizontal fluid level where they are onlypartially filled.60 A local cause of lymphatic obstruc-tion can often be identified adjacent to thelymphangiectasia, in our experience typically a pri-mary pterygium. Rarely is there active local in-flammation identified in lymphangiectasia, withmost eyes appearing white at initial presentation,presumably because the inciting inflammatory eventcausing lymphatic scarring has resolved.47 As seen inPatients 3 and 4, the finding of lymphangiectasia inrelation to a pterygium supports the contention thatinflammation and stromal changes disrupt thelymphatic drainage, resulting in localized dilatation.To exclude other causes of chemosis, baseline bloodcount, blood urea nitrogen, electrolytes, serumalbumin, and thyroid function tests are routinelychecked. Once diagnosed, lymphangiectasia can bea challenging condition to treat, as the nature of thepreceding lymphatic obstruction can rarely beidentified.

Several strategies to treat conjunctival lymphan-giectasia have been described, typically reported assmall case series. Direct excision of the affectedconjunctiva can be successful.85,92,93 Meisler et aldescribed localized resection of all involved bulbarconjunctiva down to bare sclera.65 All patientsremained asymptomatic and recurrence-free at oneyear. An earlier series where the lymphangiectasiawas simply biopsied to facilitate tissue diagnosis, thechemosis persisted, implying that the whole lesionmust be excised.47 Liquid nitrogen cryotherapy iseffective; recurrences are common, but these areamenable to retreatment.27,28 Isolated reports detail


other modalities, specifically fractionated beta-irradiation and carbon dioxide laser ablation.7,44,91

In cases of lymphangiectasia haemorrhagica, bothsurgical excision and diathermy of the abnormalcommunication between the conjunctival vesselsand lymphatics have been described.6,15,57 A re-finement of the thermal coagulation principle hasbeen reported. Lochhead and Benjamin used anArgon laser to obliterate the junction between theblood vessel and lymphatic.60 Three patients weretreated, the procedure was well tolerated, and norecurrences occurred during the follow-up period ofone year.

Rarely, after procedures that involve extensiveconjunctival manipulation such as blepharoplastyand scleral buckling, prolonged postoperative de-pendent bulbar chemosis occurs.9,62 Although noneof these reports include conjunctival histopathology,it is likely that the chemosis develops in response todamage to local lymphatics.58 In many casesspontaneous resolution occurs, presumably due tolymphangiogenesis; however, the chemosis may bepersistent.68 Enzer and Shorr emphasize that, insuch situations, stretching of the inferior fornicealligaments occurs, and these must be surgicallyreattached to the orbital floor if initial simplemeasures such as pressure patching fail.23,37 In ourseries we initially performed direct surgical excision;although more recently we have incorporated theuse of cryopreserved amniotic membrane grafts.Wide experience has been reported with such graftsin the context of ocular surface reconstruction withexcellent results.64,76 It should be appreciated thatisolated conjunctival lymphangiectasia may be iden-tified not infrequently during clinical examination.Often it is not symptomatic, but in a minority ofcases it can be a cause of persistent ocular irritation.In such situations, many patients respond to topicalsteroids, which suppress conjunctival inflammation;only in those individiuals where chronic lymphaticscarring and ectasia supervenes is surgical interven-tion indicated.

With rare conditions such as lymphangiectasia,where there are no randomized controlled trials, itcan be difficult to determine which surgical in-tervention has the best chance of success. We feelthat our technique using amniotic membrane,which empirically attempts to minimize furtherlocal tissue trauma, has much to recommend it.

Differential Diagnosis

EPITHELIAL INCLUSION CYST

Conjunctival inclusion cysts are common, ac-counting for 22.5% of all acquired epithelial lesions,

and 80% of all cystic lesions, of the conjunctiva.32

The incidence is equal between men and women,with an average age of onset of 47 years.32 They areclassified as primary or secondary, depending ontheir etiology. The primary or congenital inclusioncyst is usually located to the superomedial portion ofthe orbit and develops during the embryonal periodas the result of separation of a portion of conjunc-tival epithelial cells.41 The secondary or acquiredinclusion cyst is more prevalent than the primarycyst and is located most commonly in the supero-lateral aspect portion of the orbit. Acquired in-clusion cysts form as the result of implantation ofconjunctival epithelium underneath the stromafollowing injury or surgery, but may occur sponta-neously by the amalgamation of mucosal folds thatresult from irregularly elevated surface epitheliumin inflammatory conditions.84

Acquired inclusion cyst formation has beenreported following surgery where the conjunctivais disturbed, including strabismus surgery, vitreor-etinal surgery, cataract surgery ,and sub-Tenon’sanesthesia.10,70,90,97,99 Spontaneous inclusion cystformation has been reported in association withpterygia and in longstanding chronic vernal kerato-conjunctivitis.52,56 The cysts may present manydecades after the surgical procedure, particularlystrabismus surgery.90 They can be unilocular ormultilocular. Histopathogical examination revealsthat the cysts are lined by non-keratinizing stratifiedepithelium with occasional goblet cells. There maybe scattered chronic inflammatory cells within thesubstantia propria, and if the cyst is longstanding,foci of dystrophic calcification may be present. Thecysts are filled with clear fluid that often containsdesquamated cellular debris.87 Indications for re-moval include unacceptable cosmetic appearance,limitation in ocular motility, induced astigmatism,and ocular irritation.52,90,97 Excision biopsy is thestandard, although cauterization at the slit-lamp andNd:YAG laser ablation has been used successfully foracquired cysts.18,38,53

CYSTIC CONJUNCTIVAL NEVI

The conjunctival nevus is the most commonmelanocytic tumor of the conjunctiva and hasa benign natural history, with less than 1% de-veloping into malignant melanoma.87 A nevustypically becomes clinically apparent during the firstor second decade of life as a discrete, variablypigmented, slightly elevated lesion that may containfine, clear cysts.88

Histologically, the structure of conjunctival nevi issimilar to those found on skin, namely junctional,compound, and subepithelial. The nevus tend to be


well circumscribed, non-encapsulated with nests ofbenign melanocytes in the stroma near the basallayers of the epithelium. A unique feature ofconjunctival nevi, distinct from skin nevi, is thepresence of large number of epithelial nest andcysts.79 These cysts are found in 40--70% of allconjunctival naevi and are composed of a stratifiedsquamous epithelial lining and occasional gobletcells.42 It is hypothesised that the epithelial tissue isdragged down as the initial junctional nevus de-scends into the substantia propria and becomesa compound nevus.26 With time the intraepithelialcomponent of the nevus may be lost completely, andthus only the subepithelial component persists,resulting in a subepithelial nevus. Cysts are notedin 70% of compound nevi, 58% of subepithelialnevi, and 40% of junctional nevi.86 In children,con-junctival nevi excised because of documented rapidgrowth frequently show a marked local inflamma-tory infiltrate.103

LYMPHANGIOMA

Although a historically accepted term, lymphan-gioma literally implies a neoplasm of lymphaticorigin, these lesions are hamartomatous malforma-tions, however, and their anomalous morphogenesisdoes not produce true lymphatic channels.34

These lesions constitue a wide spectrum ofmalformations that are influenced when they occurduring embryonic embryogenesis.43,50,100 These caninvolve multiple orbital compartments, includingboth the palpebral and epibulbar conjunctiva.35,45,78

Many are symptomatic because of mass effects,hemorrhage, and pain associated with acute en-largement.33 These vascular malformations typicallybecome apparent in the first decade of life,although rarely they may manifest much later, withthe oldest presentation being in a patient aged 79.35

There is a slight female preponderance.59

Histological analysis reveals an ill-defined collec-tion of lymphatic channels infiltrating normaltissues without a capsule.35 The accumulation ofvessels is more prominent than in lymphangiectasia.There is a variable amount of stroma showingevidence of smooth muscle, thereby belying a purelylymphatic lineage, hemosiderin-laden macrophages(if subject to repeated hemorrhages), and a variablelymphocytic component.59 In some cases the lym-phocytic elements are arranged into lymphoidaggregates forming subendothelial follicularstructures.96

CONJUNCTIVOCHALASIS

Conjunctivochalasis describes the conditionwhere there is redundant, loose, non-edematous

inferior bulbar conjunctiva interposed between theglobe and the lower eyelid margin.66 It is invariablybilateral, although it may be asymmetric, being mostprevalent in the elderly.61 Mechanical disruption ofnormal tear outflow occurs from interference by theredundant conjunctiva with the inferior tear menis-cus and direct occlusion of the lower punctum.61

Patients complain of intermittent epiphora, ocularirritation or frank pain, and recurrent subconjunc-tival hemorrhage.71 Otaka and Kyu suggested thatthe redundant conjunctival folds were found at thelower-lid margin rather than the upper because ofgravity.74

Meller and Tseng propose that chronic ocularsurface inflammation causes the accumulation ofcollagenolytic enzymes in tears resulting fromdelayed tear clearance and may be linked to thedevelopment of redundant bulbar conjunctiva.66 Asubsequent study by Watanabe et al did indeed findmorphologic degenerative changes in the conjunc-tiva with fragmentation of elastic fibers and loss ofcollagen fibers in all cases, although there was noevidence of chronic inflammation.98 Instead theyhypothesised that purely mechanical forces betweenthe lid and conjunctiva impaired lymphatic flowresulting in microscopic lymphangiectasia, which inturn led to the development of conjunctivochalasis.Others have not found any evidence of lymphan-giectasia in such patients, but did find chronic tissueinflammation in association with functional nasola-crimal blockage.12,16 Fraunfelder reported one casethat presented with diffuse lymphangiectasia in theright eye and conjunctivochalasis in the left eye,demonstrating that these conditions can coexist.27

SEASONAL AND PERENNIAL ALLERGIC

CONJUNCTIVITIS

Seasonal allergic conjunctivitis (SAC), or hayfever, is the most common form of ocular allergicdisease and is associated with sensitization andexposure to environmental allergens, in particulargrass and ragweed pollens.63 Perennial allergicconjunctivitis (PAC), typically triggered by housedust mites and animal dander, is considered a lesssevere variant of SAC characterized by year-roundsymptoms, but with seasonal exacerbations experi-enced by 79%.17 Both conditions have an onset inchildhood or early adulthood with no sex pre-dilection. Affected individuals often have a historyof atopy.31 Symptoms are invariably bilateral,l butmay be asymmetric and consist of red, itchy eyes,with associated burning discomfort and waterydischarge. Both SAC and PAC are examples of a type1 IgE-mediated hypersensitivity reaction. The pri-mary inflammatory cells involved in ocular allergy


are mast cells, which reside within the substantiapropria.73

Clinical examination reveals mild conjunctivalhyperemia with a papillary reaction. In severe casesthere is chemosis as a result of increased tissue fluid,most marked in the bulbar and lower tarsalconjunctiva. This gives the eyes a characteristicglassy appearance. Although rarely performed inclinical practice, histological analysis of conjunctivalspecimens from SAC and PAC patients demonstratesincreased numbers of mast cells in the stroma, andinfrequently within the epithelium itself.4 Theremay be stromal edema and increased numbers ofconjunctival goblet cells.63

ATAXIA-TELANGECTASIA

Ataxia telangectasia (AT; Louis-Bar syndrome) isa rare autosomal recessive disorder characterized byearly-onset progressive cerebellar ataxia, immuno-deficiency, dysarthria, oculocutaneous telangiecta-sia, and abnormal ocular motility (nystagmus,pursuit and saccadic abnormalities, strabismus),and poor convergence and accommodation.25 Inthe United States the incidence has been reportedas 1in 30,000 live births.94 The responsible gene,ATM (AT mutated), located on chromosome 11, wasidentified in 1995.80 The telangectasia are alwaysbilateral and are most prominent on the interpalpe-bral conjunctiva.25 These vessels increase in tortu-osity and become progressively more dilated overthe years.77 Telangiectasia of the skin may sub-sequently develop; the regions most commonlyaffected are the malar eminence of the face andpinnae of the ear. Unlike lymphangiectasia conjunc-tivae hemorrhagica where the blood-filled vesselsappear then clear within a matter of days, in AT theyare persistent and progressive. The vascular changesappear to have no significant effect on ocularcomfort in most patients, although some arephotophobic.25 Histopathological analysis of bulbarconjunctival tissue from AT patients demonstratesincreased numbers of blood vessels and greatervariability in vessel caliber than control tissue fromthe ipsilateral inferior fornix.77

Summary

Conjunctival lymphangiectasia has received scantattention in the medical literature, yet incidentalsausage-like conjunctival cystic lesions are not in-frequently seen during anterior segment examina-tion. These require no intervention unless theyresult in persistent ocular surface irritation that isrefractory to topical anti-inflammatories and lubri-cation. The vast majority are thought to represent

secondary lymphangiectasia, developing as a conse-quence of a prior inciting stimulus, resulting inpersistent local lymphatic scarring or distal mechan-ical outflow obstruction. Typically the patient doesnot recall this preceding event, nor is it clinicallyapparent. True primary conjunctival lymphangiec-tasia is rare and is only seen where there isa generalized failure of lymphatic development, asa result of deranged VEGFR-3 signaling.

Method of Literature Search

A search of the PubMed database 1966--2010 wasconducted using various combinations of the keywords conjunctiva, lymphangiectasia, lymphangiectasis,lymphatics, chemosis, swelling, cyst, and hemorrhage.Articles in all languages were considered, providedthat the non-English articles included Englishabstracts. Relevant articles that were cited in thereference lists of the retrieved articles were alsoincluded.

Disclosure

The authors reported no proprietary or commer-cial interest in any product mentioned or conceptdiscussed in this article.

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Reprint address: Sathish Srinivasan, Department of Ophthal-mology, 3rd Floor, Ayr Hospital, Dalmellington Road, Ayr, KA66DX, Scotland, United Kingdom. e-mail: [email protected].

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conjunctival lymphangiectasia: a report of 11 cases and review of literature

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