Pterygium
Introduction
Pterygium (pleural: pterygia) is a prevalent ocular surface lesion, traditionally described as an encroachment of altered bulbar conjunctiva onto the cornea.1 Its name originates from the diminutive of πτερυζ, (Greek, small wing) referring to its characteristic wing-like growth pattern.2 Pterygium is an enigma and many theories have been proposed as to its pathogenesis. Historically, pterygia were considered to be degenerative lesions exemplified by degradation of Bowman’s layer and elastosis. The current view is that pterygium is an aberrant wound healing process, characterized by centripetal growth of a leading edge of altered limbal epithelial cells, followed by a squamous metaplastic epithelium with goblet cell hyperplasia and an underlying stroma of activated, proliferating fibroblasts, neovascularization, inflammatory cells, and extracellular matrix remodeling.3
Pterygia and other sun-related eye diseases (the ophthalmohelioses) pose a significant health problem to many communities. In Australia, with a population of approximately 22 million, it has been estimated that approximately 60 000 general practice visits annually include care for pterygia.4 The direct annual cost of pterygium in Australia is AU$8.3 million and this is likely to be an underestimation. Pterygium is often prevalent in developing countries with scarce health resources and in this setting can be a blinding disease.5,6 In biological terms, if conjunctival/limbal autografting is performed, 50% of the limbus and associated stem cells can be affected. Given the importance of stem cells in long-term corneal maintenance, pterygium is a condition of great significance.
Historically, the consequences of pterygium on the ocular surface have also been underestimated and the disease trivialized. Boxes 18.1 and 18.2 summarise associated vision loss and primary and secondary complications of pterygia. Systemic associations, such as polymorphous light eruption, porphyria cutanea tarda and skin malignancy7 have not been well recognized, yet pterygium is almost certainly a significant biomarker for substantial ultraviolet ocular and body surface insolation. Progressive pterygia can lead to complications, such as astigmatism and increased higher-order aberrations. These aberrations are decreased significantly at 2 weeks after surgery and remain relatively stable, yet they remain at levels much higher than in normal eyes.8 A possible cause may relate to the observation that invasion of the pterygium head deep to Bowman’s membrane, predicts postoperative corneal opacity/scarring.9 With ready availability of aberrometry and optical coherence tomography, a consideration is to operate before such changes are established. Given these findings, the era of refractive pterygium surgery may have arrived.
Box 18.2 Ocular Assocations of Pterygium
The association with dry eye is also well known. A twofold increased risk of dry eye symptoms exists in pterygium patients.10 While a direct mechanical mechanism is obvious, advances in our understanding of the inflammatory basis of dry eye syndrome11 suggest an indirect effect of inflammatory mediators in pterygium, resulting in a ‘pseudo-dry-eye state.’
Clinical Features
The classic appearance of a pterygium is that of a wing-shaped fibrovascular lesion extending from the bulbar conjunctiva onto the cornea (Fig. 18.1). Pterygia may be primary or recurrent, unilateral or bilateral, and present nasally or temporally in either or both eyes. They occur invariably in the palpebral fissure, predominantly at the nasal limbus, while temporal pterygia are less common and rarely found in isolation (Fig. 18.2).12 Anatomically, the pterygium may be divided into three parts. The ‘head’ consists of the apex enclosed by an avascular cap, the ‘neck’ refers to the region between the head and limbus overlying the cornea, and the ‘body’ is the portion overlying the sclera.13 When observed by slit lamp, gray ‘islets’ may be present within the cap at the advancing edge of the pterygium (Fig. 18.3). First described by Fuchs, these ‘flecks’ or Fuchs’ islets represent the most advanced parts of the pterygium, which coalesce over time with the migrating boundary, to form tongue-shaped extensions at the apex.14 Iron deposition in the corneal epithelium, just apical to the head of the pterygium, is known as Stocker’s line.15
Figure 18.1 Primary pterygium.
Symptoms
Dry eye symptoms such as redness, irritation and blurred vision are common in pterygium.10 Reduced tear break-up time and abnormal tear-ferning have been reported with partial restoration of tear function once the pterygium is removed.16 Pterygium-associated visual disturbances are summarized in Box 18.1.
Histopathology
Topographic studies of the pterygium show that it is an epithelium-covered protuberance of connective tissue projecting over the ocular surface with an apex that extends in the direction of growth.17 The epithelium is characterized by centripetal growth of a leading edge of altered limbal epithelial cells,18 followed by abnormal conjunctival epithelium, with features of goblet cell hyperplasia and squamous metaplasia (Fig. 18.4A).19 The underlying connective tissue stroma consists of activated, proliferating fibroblasts and blood vessels.20 Chronic mixed inflammatory infiltrates may be present, comprising lymphocytes, plasma cells, mast cells, Langerhans cells, monocytes and macrophages, with neutrophils present in acutely inflamed lesions (Fig. 18.4B). Immunoglobulin (IgG and IgE) deposition along the basement membrane,21 aberrant expression of HLA-DR22 and adhesion molecules (ICAM-1 and VCAM-1)23 have also been reported. Extracellular matrix changes are prominent features of pterygium. These include dissolution of Bowman’s layer at the migrating head and accumulation of elastotic material within the stroma (Fig. 18.4C).
Differential Diagnosis
The differential diagnosis of pterygium includes pinguecula, pseudopterygium, and various conjunctival tumors. Although there are some similarities, these entities may be distinguished by morphology and clinical behavior. Of note, it is critical to consider limbal/conjunctival malignancy given that both pterygium and pinguecula may harbor epithelial dysplasia.24
Pinguecula
Pinguecula (pleural: pingueculae) appears as an elevated yellow white plaque in the conjunctiva adjacent to the nasal or temporal limbus. They are distinguished from pterygia by their lack of corneal invasion, possibly due to an intact limbal barrier. Although most pinguecula are slow growing with a benign course, it is recognized that some may evolve into pterygia.14 The histological changes of pinguecula are similar to those in pterygium and comprise predominantly subepithelial elastosis, hyaline degeneration, eosinophilic and basophilic concretions,25 squamous and metaplastic changes of the epithelium.26
Pseudopterygium and Other Inflammatory Conditions
Pseudopterygium originates from conjunctival adhesions to corneal defects as a result of trauma, previous surgery or inflammation. A key feature that differentiates pseudopterygia from true pterygia, is that the former may occur anywhere on the corneal circumference, whereas the latter are typically limited to the 3- and 9-o’clock position. The pseudopterygium has a broad, flat leading edge at its point of attachment, with the bulk of the lesion not adherent to the underlying cornea.27 Conditions that may be associated with pseudopterygium include Fuchs’ superficial marginal keratitis and Terrien’s marginal degeneration.28 Other inflammatory conditions to be considered include phlyctenular keratoconjunctivitis, nodular episcleritis and actinic granulomas.
Conjunctival Tumors
Benign and malignant tumors of the conjunctiva may be confused with pterygia. These include limbal dermoid, papilloma, amyloidosis, lymphoma of the conjunctiva, non-pigmented nevi, melanoma, conjunctival intraepithelial neoplasia and squamous cell carcinoma.29 Of special consideration are pre-neoplastic lesions, such as ocular surface squamous neoplasia30 and primary acquired melanosis,31 which may coexist with pterygia.32 A high index of suspicion should be maintained when managing pterygia with an atypical appearance. Given these lesions may not be clinically obvious, histological examination of all excised pterygia is recommended.
Epidemiology
Pterygium is present worldwide with prevalence rates depending on the age group and geographical location. In Cameron’s survey of the world’s distribution of pterygia,33 higher rates were observed in those living in peri-equatorial countries, including hot, dry and dusty climates. This is supported by an Australian study that showed a prevalence up to 15.2% in Aborigines living in the northern territories, compared to 4.5% in those living in the southern states. A positive correlation was seen with lifetime sun exposure.34 However, the high incidence of pterygia in Tibetans (14.5%)35 and Mongolians (17.8%)36 living in high altitudes but away from the equator, contradicts these pterygia epidemiology studies. The high incidence in Eskimos in Greenland (8.6%)37 and watermen in Chesapeake Bay (16.7%)38 results from reflected sunlight off snow or water. From these studies, it is clear that cumulative ultraviolet (UV) light exposure is a major risk factor for pterygia. Other risk factors include family history, increasing age, male gender, and rural residency, while wearing glasses or a hat have a protective effect.39,40 Certain groups, such as welders41, laborers and outdoor workers have increased incidence of pterygium, as a result of their occupational exposure.42 Pterygia are also more common in sawmill workers exposed to dusty environments, where chronic irritation and microtrauma is hypothesized to play a role in these cases.43 More recently, exposure to arsenic44 and petrochemicals45 have also been linked to pterygia.
Pathogenesis
The pathogenesis of pterygium is poorly understood. The popular view of pterygium as a degenerative condition was based on histological evidence of the extracellular matrix degradation. However, this is contradicted by its invasive growth habit and propensity to recur when excised. In reality, both degenerative and hyperplastic processes are present in pterygium,1 with multiple mechanisms contributing to its formation (Fig. 18.5). These mechanisms may be divided into inherited factors, environmental triggers (UV light, viral infections) and factors that perpetuate its growth (cytokines, growth factors and matrix metalloproteinases). Cumulative DNA damage and activation of antiapoptotic factors may also contribute to the proliferative phenotype of pterygium, while the contribution of stem cells and neurogenic inflammation will also be discussed.
Ultraviolet Light
The role of chronic UV exposure in the pathogenesis of pterygium is well supported by epidemiological studies and its clinical associations with other UV-related conditions, such as photo-aged skin, cataracts, climatic droplet keratopathy, squamous cell and basal cell carcinomas.32 The curious growth habit of the pterygium and it predilection for the medial limbus is explained by our model of peripheral light focusing effect of the anterior chamber, which concentrates incidental light by 20× onto the medial limbus (Fig. 18.6).46 Chronic focal UV damage to this region is hypothesized to activate limbal stem cells, leading to formation of a pterygium.47 Also intriguing is autofluorescence of pterygia under UV light (300–400 nm) (Fig. 18.7),48 which may precede visible signs of an ocular surface lesion (Fig. 18.8).49 The cause for autofluorescence is unknown but we speculate that it may represent altered collagen or cellular activity as a result of solar damage.48 Additionally, pterygia share certain histological features with photo-aged skin including epidermal proliferation, inflammatory infiltrates, activated fibroblasts and extracellular matrix remodeling.3 To follow, we will discuss UV activated molecular mechanisms that are involved in the pathogenesis of pterygium.
Oxidative Stress and Growth Factor Receptor Signaling
UV-induced oxidative stress has been implicated in the pathogenesis of pterygium. Supportive evidence include the presence of 8-hydroxydeoxyguanosine (a DNA photo-oxidation product)50 and malondialdehyde (a product of lipid peroxidation),51 inducible nitric oxide synthase and nitric oxide (NO)52 in pterygium tissue. Reactive oxygen species (ROS), such as NO may act as a pro-angiogenic factor by mediating vascularization,53 endothelial proliferation and migration,54 MMP-2 activation,55 and potentially, MMP expression patterns in pterygia. Other ROS, such as hydrogen peroxide are known to activate epidermal growth factor receptors (EGFRs) and subsequent downstream signaling via the mitogen-activated protein kinase (MAPK) pathways, such as extracellular signal-regulated kinase (ERK), c-jun amino-terminal kinase (JNK) and p38.56 In pterygium cell cultures, UV activated JNK and p38 induces expression of pro-inflammatory cytokines,57 while activation of ERK is responsible for induction of MMP-1.58,59
Pro-inflammatory Cytokines and Immunological Mechanisms
Epidemiological studies have hinted that chronic inflammation from desiccation, chemical exposure and microtrauma may play a role in the pathogenesis of pterygia. Wong suggested a mechanism where inflammation at the junction of the conjunctival blood vessels and Bowman’s membrane degraded proteins which then act as angiogenic factors.60 The presence of mixed chronic inflammatory infiltrates including T lymphocytes, plasma cells, mast cells, Langerhans cells, monocytes, and macrophage supports the conclusion that immunological mechanisms21 might be involved. Although immune infiltrates may contribute to inflammation in pterygia, their presence are likely a consequence of cytokines and other pro-inflammatory mediators present in pterygium (Box 18.3).3 Interleukins (IL-1, IL-6, IL-8) and tumor necrosis factor-alpha (TNF-α) are known to be induced by UV light61 and NF-κB, signaling that is activated in pterygia.62,63 Their presence mediates influx of immune cells and induction of MMP expression in pterygia, while IL-4 may mediate fibrosis in recurrent lesions.64 Another UV-inducible enzyme that is overexpressed in pterygia is cycloxygenase-2 (COX-2), which converts arachidonic acid into prostaglandin.65 Its expression is associated with the anti-apoptotic factor survivin.66 COX-2 induces MMP-1 and MMP-9 in organ-cultured corneas,67 and may also contribute to elevated MMP expression in pterygia. S100 proteins are calcium-binding proteins that have roles in wound healing, inflammation and cancer,68 and have recently been described to be elevated in pterygium tissue69 and in the tears of patients with pterygia.70 The functional significance of S100 proteins in pterygia requires further study. However, their up-regulation may reflect induction by UV, cytokines or other environmental stressors.71,72 Stem cell factor (SCF) is also elevated in the plasma and ocular tissues of patients with pterygia.73,74 SCF attracts and induces maturation of mast cells,73 and their presence may promote fibrosis and neovascularization in pterygia.75 Langerhans cells have also been observed in pterygium tissue by immunohistochemical76 and in vivo confocal microscopy.77 It is speculated that a higher level of antigenic and mitogenic exposure,76 or the presence of cytokines in pterygia, might have aided in their recruitment and maturation.77 The role of Langerhans cells in pterygium pathogenesis requires further study but it was hypothesized that Langerhans cells may be involved in T-cell recruitment.78
It is interesting to note that while clinical evidence supports the notion that persistent inflammation may lead to postoperative recurrence,79 the quantity of infiltrating T cells in pterygia specimens did not correlate with clinical parameters, such as severity of inflammation or preoperative use of topical steroids or non-steroidal anti-inflammatory drugs.80 Additionally, recurrence was not predicted by histological appearance.81 This implies that inflammation does not act alone and that other factors may also contribute to recurrence of a pterygium.
Fibroangiogenic Growth Factors
Growth factors and their receptors have been reported in pterygia (Table 18.1). They serve to induce proliferation and/or migration of epithelial cells, fibroblasts or vascular cells, which contribute to hyperplasia, fibrosis and angiogenesis in pterygium.3,81
Pro-fibrotic cytokines and growth factors expressed in pterygia include IL-1, TNF-α, CTGF, EGF family, FGF-2, PDGF, and TGF-β.82 Of these, TGF-β is particularly important since it induces myofibroblast differentiation, epithelial mesenchymal transition and alters synthesis of extracellular matrix components.83 Aberrant TGF-β signaling84,85 is thought to contribute to fibrosis in pterygia, and its suppression by amniotic membrane86 may explain the efficacy of this treatment.
Elevated pro-angiogenic factors (IL-8, TNF-α, FGF-2, HB-EGF and VEGF) combined with lack of angiogenic inhibitors (PEDF and thrombospondin-1) encourage prominent neovascularization in pterygia.82 VEGF, a major pro-angiogenic factor, is elevated in the tears, plasma and ocular tissues of patients with pterygia.74,87 VEGF expression in pterygia may be driven by multiple stimuli (UV, hypoxia, cytokines and growth factors) and probably represents a common pro-angiogenic pathway.3,82
More recently, neurotrophins and their receptors have been investigated in pterygia, where nerve growth factor (NGF), ciliary neurotrophic factor and neurotrophin-4/5 were reported to be elevated. In addition, the high- and low-affinity NGF receptors (TRKA and NGFR, respectively) have also been described in epithelial cells and blood vessels of pterygia.88–90 A pro-angiogenic role for neurotrophins is suggested by the correlation of NGF – TRKA staining with microvessel density in pterygia.89
Matrix Metalloproteinases and Extracellular Matrix Remodeling
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade components of the extracellular matrix and cell surface molecules. These enzymes are counterbalanced by endogenous inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). MMPs participate in ocular physiology, pathophysiology, and are key mediators of photo-aging, where they regulate proliferation, cell migration, inflammation and angiogenesis.91 Overexpression of MMPs relative to TIMPs is thought to contribute to the invasive phenotype of pterygia, where MMP expression may be induced by UV light, cytokines (IL-1 and TNF-α) and growth factors (EGF and TGF-α).3,82 Of interest is the association of MMP-2 and -9 with disease progression,92 suggesting that MMPs may be an attractive target for management of this disease.
Additional to extracellular matrix breakdown, altered synthesis of matrix components have been reported in pterygia, including tropoelastin,93 glycosaminoglycans,94 hyaluronic acid,95 periostin,64 fibulin-2 and fibulin-3.96 Altered matrix components may increase the bioavailability of heparin-binding growth factors and cytokines (e.g. IL-8, FGF-2, HB-EGF, VEGF, PDGF and TGF-β) which are normally sequestered by the extracellular matrix and released upon its degradation.97
Inherited Factors
Although environmental exposure plays a major role in the pathogenesis of pterygia, inherited factors may influence its development. Supporting this concept are families with pterygia where ocular disease often presents at a younger age and with an autosomal dominant inheritance pattern.98,99 Individuals with xeroderma pigmentosum,100 single nucleotide polymorphisms in 8-oxoguanine glycosylase 1 (hOGG1),101 X-ray repair cross-complementing-1 (XRCC1)102 or X-ray repair cross-complementing-6 (XRCC6),103 have been associated with pterygium development, suggesting defective DNA repair may contribute to the pathogenesis of this condition. Genetic variants in glutathione S-transferase M1 (GSTM1)104 and cytochrome P4501A1 (CYP1A1),105 enzymes that metabolize polycyclic aromatic hydrocarbons, are reported to be associated with pterygia. (See Box 18.4 for details on gene association studies in pterygia.) The CYP1A1 MspI polymorphism, in particular, is associated with accumulation of Benzo[a]pyrene 7,8 diol-9,10-epoxide (BPDE)-like DNA adducts in pterygium tissue,105 implying interactions between genetic and environmental factors in this condition.
Viral Infections
Based on Knudson’s hypothesis of cancer as a result of cumulative DNA mutations, Detorakis et al. proposed a role for oncogenic viruses in the pathogenesis of pterygia in their two-hit model.106 The ‘first hit’ is attributed to a genetic predisposition for pterygia or acquired DNA damage from UV exposure. The ‘second hit’ may be additional UV exposure or caused by infections, such as human papillomavirus (HPV) or herpes simplex virus (HSV).106 Evidence supporting HPV in the pathogenesis of pterygia include the detection of HPV subtypes 1, 2, 6, 11, 16, 18, 37, 52, 54 and HPV90 in pterygium tissue. However, the prevalence rate (0–100%) varies widely between studies.107 These findings might be explained by variable HPV infection rates between populations108 or methodological differences. A possible contributing mechanism might be the inactivation of p53 by viral oncoprotein (HPV 16/18 E6).109 Studies on HSV have been restricted to two centers with prevalence of 22% in Greece110 and 5% in Taiwan,111 and co-infection with HPV was associated with postoperative recurrence in one study.110 Given the limited and inconsistent data, viral infection is likely not an absolute requirement for pterygium formation.
Genetic and Epigenetic Changes
Some authors favor the idea that cumulative DNA damage106,112 might be involved in the pathogenesis of pterygia. Additional to the presence of 8-hydroxydeoxyguanosine (8-OHdG)50 and BPDE-like DNA adducts105 in pterygia of susceptible individuals, a number of genetic changes have been described including loss of heterozygosity, microsatellite instability,113 and mutations in Kirsten-ras114 and p53 genes.109,115,116 Of these, only p53 mutations have been studied extensively.
The tumor suppressor protein p53, is often referred to as the ‘guardian of the genome’. P53 is normally found in low levels due to its short half-life. In the presence of DNA damage, it stabilizes, translocates to the nucleus, inducing cell cycle arrest, DNA repair or apoptosis.117
