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  • The American Journal of Pathology, Vol. 178, No. 2, February 2011

    Copyright 2011 American Society for Investigative Pathology.

    Published by Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.ajpath.2010.10.037Stem Cells, Tissue Engineering, and Hematopoietic Elements

    Ophthalmic PterygiumA Stem Cell Disorder with Premalignant FeaturesJeanie Chui,* Minas T. Coroneo, Lien T. Tat,

    Roger Crouch, Denis Wakefield,*and Nick Di Girolamo*From the Inflammation and Infection Research Centre,* School

    of Medical Sciences, University of New South Wales, Sydney; the

    Department of Ophthalmology, and the South Eastern Area

    Laboratory Services, Prince of Wales Hospital, Randwick,

    Sydney; and Ophthalmic Surgeons, Randwick, Sydney,


    Pterygia are common ocular surface lesions thought tooriginate from limbal stem cells altered by chronic UVexposure. Traditionally regarded as a degenerative con-dition, pterygia also display tumor-like features, such asa propensity to invade normal tissue and high recur-rence rates following resection, and may coexist withsecondary premalignant lesions. This study was initi-ated to determine the rate of concurrent ocular surfacediseases in patients with pterygia recruited from thepractice of a single surgeon operating in a Sydney met-ropolitan hospital. One hundred pterygium specimenswere histopathologically reviewed and selected caseswere immunohistochemically assessed to confirm di-agnosis. Along with previously documented typicalfeatures including epithelial proliferation, goblet cellhyperplasia, angiogenesis, inflammation, elastosis,stromal plaques, and Bowmans membrane dissolution,we identified five cases of ocular surface squamous neo-plasia, six cases of primary acquired melanosis, twocompound nevi (one suspect invasive melanoma), andone dermoid-like lesion. In 18 specimens, clusters ofbasal epithelial cells that coexpressed cytokeratin-15/-19 and p63- were identified at the head of thepterygium, coinciding with clinical observation ofFuchs flecks. Our data show that significant preneo-plastic lesions may be associated with pterygium andthat all excised pterygia should undergo histologicalexamination. The presence of p63--positive epithe-lial cell clusters supports the hypothesis that pterygiadevelop from limbal epithelial progenitors. (Am J

    Pathol 2011, 178:817827; DOI: 10.1016/j.ajpath.2010.10.037)Pterygium is a wing-shaped ocular surface lesion tradition-ally described as an encroachment of bulbar conjunctivaonto the cornea.1 Historically, pterygia were considereddegenerative lesions, exemplified by degradation of Bow-mans layer and elastosis. Currently, however, pterygia aredescribed as a proliferative disorder resembling an ab-errant wound healing response.2 Histopathologically,pterygia are characterized by a hyperplastic, centripe-tally directed growth of altered limbal epithelial cells ac-companied by Bowmans layer dissolution, epithelial-mesenchymal transition, and an activated fibroblasticstroma with inflammation, neovascularization, and matrixremodeling, mediated through the concerted actions ofcytokines, growth factors, and matrix metalloprotei-nases.29 Despite advances in understanding of itspathogenesis, pterygium remains an ophthalmic enigma.Intriguingly, pterygia have a predilection for the nasallimbus and affect only humans, possibly reflecting theunique ocular morphology of humans, compared withnonhuman primates and other animals.10 Although thereis no consensus regarding the pathogenesis of pterygia,epidemiological evidence,1114 its association with sun-re-lated disorders such as pinguecula and cataracts,15 cli-matic droplet keratopathy,16 and squamous cell and basalcell carcinomas,17,18 together with our in vitro studies,58

    support the concept that UV radiation plays a major role indevelopment of pterygium.19 Furthermore, the limbal predi-lection may be explained by the phenomenon of peripherallight focusing, in which incidental light passes through theanterior chamber and is focused at the distal (nasal) limbuswhere limbal stem cells (LSCs) reside.20

    A healthy corneal surface is maintained by self-renewing,lineage-specific stem cells (SCs) that reside in the limbus, anarrow annular transition zone that circumscribes the cor-nea. This regenerative capacity is regulated by exquisiteprograms that govern stem cell quiescence, proliferation,

    Supported by a Career Development award (no. 455358, to N.D.) from theNational Health and Medical Research Council of Australia.

    Accepted for publication October 14, 2010.

    Address reprint requests to Nick Di Girolamo, Ph.D., Inflammation andInfection Research Centre, School of Medical Sciences, University of NewSouth Wales, Sydney, 2052 NSW, Australia. E-mail: n.digirolamo@unsw.




  • 818 Chui et alAJP February 2011, Vol. 178, No. 2migration, and differentiation. Failure to maintain a normalmicroenvironment as a result of extrinsic (eg, UV radiation)or intrinsic (eg, cytokines) signals can result in the develop-ment of ocular disorders.26,19,21,22 The importance of anintact limbus and its stem cells was recognized four de-cades ago by Davanger and Evensen,23 who proposed thatpterygia represent a specific zone of LSC deficiency. Ourhypothesis for pterygium development takes into accountperipheral light focusing2,9,19,20 at the nasal limbus, whichactivates and/or mutates LSCs, resulting in clonal expan-

    Figure 1. The role of cumulative UV radiation exposure in pterygiumdevelopment. A: Model for the pathogenesis of pterygium: focal limbaldamage from UV radiation triggers migration of altered LSCs toward thecentral cornea. B: In total LSC deficiency, damage to the limbal niche ordepletion of stem cell reserves results in conjunctivalization of the corneafrom all directions. C: Model of how ocular surface squamous neoplasiaand melanoma might arise from pterygia. Question marks with path-ways indicate absence of direct supporting clinical or experimental evi-dence. D: Bisection and orientation of pterygium specimens as assessedin the current study.

    Table 1. Premalignant Ocular Disease Reported in Association w

    References Study population Tis

    Sevel and Sealy31 Cape Town, South Africa pterygia

    Clear et al17 Malawi pinguecptery

    Erie et al34 Mayo Clinic, Minnesota pterygiaPerra et al33 Ecuador pterygia

    Hirst et al32 Queensland, Australia pterygiaPAM, primary acquired melanosis; OSSN, ocular surface squamous neoplassion, local cell proliferation, and invasion into the cornea(Figure 1A). Alternatively, focal UV radiation may destroythe LSC repository, which acts as a barrier that segregatescornea from conjunctiva, thereby opening the flood gatesfor conjunctival ingress and pterygium formation. Further-more, an intrinsic weakness in the LSC reserves is impliedby less prominent limbal palisades in the nasal and tempo-ral limbus,24,25 suggesting that these regions might bemore susceptible to damage and less likely to undergoeffective repair. An analogous mechanism may occur inpatients with total LSC deficiency,26 in which the absence ofLSCs allows conjunctival invasion of the cornea to occurfrom 360 degrees (Figure 1B). In support of this posit, con-secutive rounds of limbal excision affected wound healing,encouraged neovascularization, and promoted conjunctivalingress in rabbit corneas.27

    Ophthalmologists have traditionally regarded pterygiaas benign lesions, because they grow slowly. Unless apterygium is sufficiently large as to obscure the visualaxis or causes astigmatism, decisions to treat are oftenbased on a patients cosmetic concerns. An argumentagainst this view, however, is the local invasiveness andhigh rate of recurrence when pterygia are inappropriatelymanaged.28 Current management strategies for ptery-gia involve surgical excision, followed by wound clo-sure with grafts or by application of adjunctive therapyto the bare scleral bed.29,30 Once excised, pterygia arecommonly discarded without histological evaluation.This practice is not recommended, in the face of re-ported identification of unsuspected and potentiallymalignant secondary disorders in association withpterygia3133 (Table 1). These studies suggest thatpterygia might have the propensity to evolve into pre-cursors of squamous cell carcinoma and malignantmelanoma of the ocular surface (Figure 1C).

    In this study, we examined the histopathology ofpterygia from patients treated by a single surgeon op-erating in a metropolitan hospital in Sydney, Australia.Histological features of pterygia and concurrent oculardiseases were recorded. All unusual cases were re-viewed by an experienced anatomical pathologist andwere further investigated by immunohistochemicalmethods. Additionally, we describe novel cell clustersin some pterygia that expressed putative LSC markers.

    rygium and Pinguecula

    Sample sizeAssociated ocular

    disease %

    n 100 squamous cell carcinoma 12carcinoma in situ 17

    d n 167 hyperplasia or milddysplasia


    moderate dysplasia 11.4carcinoma in situ 12.6

    n 92 carcinoma in situ 9.8n 80 PAM without atypia 6.3

    PAM with atypia 2.5nevi 2.5

    n 533 OSSN 9.8ith Pte


    ula angiaia.

  • Ophthalmic Pterygium 819AJP February 2011, Vol. 178, No. 2These cell clusters may provide the first histologicalevidence supporting the view that pterygium is a dis-ease of stem cell origin.

    Materials and Methods


    Patients undergoing routine pterygium excision surgeryby a single surgeon (M.T.C.) were recruited from Princeof Wales Hospital, Randwick, Sydney, Australia, and fromthe surgeons private practice. Clinicodemographic fea-tures recorded included patient age and sex and location(nasal or temporal) and type of lesion (pr