Textbook of Pterygium Management Namrata Sharma, Tushar Agarwal, Shikha Gupta
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section I
1Pterygium: What, Why and When?
CHAPTER
  • 1. Etiopathogenesis of Pterygium
    • Shikha Gupta, Tushar Agarwal
  • 2. Workup of a Case of Pterygium
    • Shikha Gupta, Tushar Agarwal2

Etiopathogenesis of PterygiumCHAPTER 1

Shikha Gupta,
Tushar Agarwal
Pterygium development is a multifactorial process, which involves defects associated with genes involved in deoxyribonucleic acid (DNA) repair, migration, proliferation and angiogenesis. Multiple causative factors are implicated in the pathogenesis of pterygium including ultraviolet (UV) radiation, human papillomavirus (HPV) infection, inflammation, chronic irritation, angiogenesis, lymphangiogenesis and genetic predisposition. The likely factors contributing to the development of the disease are listed.
 
Ultraviolet Radiations
Ultraviolet radiations (UV) B radiations are absorbed by the cornea. Stemming from this, there is evidence that UV B radiations play a pivotal role in the pathogenesis of pterygium. Upregulation of oxidative stress contributes to the development of pterygium. Exposure to UV B radiations results in production of reactive oxygen species which damage the corneal and conjunctival tissues at multiple sites. High oxidative stress within the pterygium tissue is indicated by an increased concentration of malondialdehyde and nitric oxide along with lower levels of superoxide dismutase enzyme which is an antioxidant. The radiations act on epidermal growth factor (EGF) receptors and cause subsequent extracellular signal regulated activation of mitogen activated protein kinase pathways. The downstream elements of this pathway involve the nuclear factor kB (NF-kB) and other targets, the expression of which is seen in response to inflammatory cytokines like tumor necrosis factor alpha (TNF-α). Recent evidence shows that exposure to UVA radiation may also similarly upregulate urokinase plasminogen activator (uPA) which subsequently increase the activity of phosphorylated extracellular signal-regulated kinases (ERKs) and c-Jun amino-terminal protein kinase (JNK) in cultured pterygeal fibroblasts. These fibroblasts are more sensitive to UVA induced uPA activation when compared to normal fibroblasts. Pterygium epithelium show high immunopositivity for cyclic AMP response element-binding protein (CREB), which is an upstream element for many factors involved in the pathogenesis of pterygium. The activation of protein kinases induces upregulation of matrix metalloproteinases (MMP 1): collagenase, gelatinase (MMP 2 and MMP 9) as well as others like MMP 3 and 10 within pterygium epithelial cells. Matrix metalloproteinases allow the pterygium epithelial cells to invade the corneal epithelium through dissolution of Bowman's membrane. There is down-regulation of tissue inhibitor of metalloproteinases (TIMP) which further increases pterygeal ability for cellular invasion and migration.
Chronic UV exposure causes up-regulation of growth factors like IL-4, IL-6 and heparin-binding epidermal growth factor (HB- EGF), causing dysplasia of limbal epithelial cells into pterygium epithelial cells. An increased concentration of these mediators in conjunction with declining urokinase plasminogen activator (uPA) levels act to intensify the inflammatory cascade. An enhanced expression of the matricellular protein SPARC (secreted protein acidic and rich in cysteine also known as osteonectin or BM-40), and other extracellular matrix proteins is seen within the stroma of pterygium along with colocalization of, and MMP-3. An increased expressivity has been observed for collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), cyclin D1, Ki-67, vimentin, survivin, p63, and MMPs within the pterygium body; however the exact role of these mediators in the final pathogenesis of pterygium is still investigational.
Permanent DNA damage can occur following exposure to UVB radiations; suggested by the presence of thymine dimers localized in the basal layer of epithelium and anti-thymine dimer antibodies expressed by the endothelium and perivascular layers. Thymine dimers are also implicated in recurrence of pterygium. Immune localization of 8-hydroxydeoxyguanosine, which is a sensitive marker for DNA damage, within the nuclei of pterygium epithelium provides an additional evidence for DNA damage. Loss of heterozygosity of p53 tumor suppressor gene has also been reported within the epithelial nuclei of pterygia. The normal sequence of events upon DNA damage is repair of UV-induced abnormal DNA by elements of base excision repair (BER) or the nucleotide excision repair (NER) gene systems. Development of pterygia occurs because of parallel defects at the level of DNA repair. Genetic polymorphism in X-ray repair thus increasing the relative risk has been observed in pterygium tissue at cross complementary 1 (XRCC1) genotype (Arg399 Glu) which is a BER gene.4
 
Angiogenesis and Inflammation
Vascular proliferation within the conjunctiva is also believed to contribute to the pathogenesis of pterygium. Research is ongoing to investigate the role of pro-angiogenic mediators and growth factors like basic fibroblast growth factor (b-FGF), prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in the causation of pterygium. It is hypothesized that endothelial progenitor cells derived from bone marrow stem cells under the influence of VEGF and other cytokines undergo transformation into pterygium cells. Till date, primary pterygia have shown higher than normal concentration of CD 105 microvessel density, VEGF, VEGF receptor-2, transforming growth factor beta-2 (TGF-β2) and erythropoietin receptor (EPO-R).
Additionally, postoperative recurrence shows positive correlation with VEGF receptor concentration within pterygium tissue suggesting that VEGF and other vascular mediators might potentially mediate recurrence. Furthermore, angiogenesis is mediated by coupling of increased angiogenic mediators along with decreased antiangiogenic proteins. Lower than normal concentration of thrombospondin-1 and PEDF, an antiangiogenic mediator have been localized from pterygia compared to healthy conjunctiva.
Additionally pterygium epithelial as well as endothelial cells of stromal microvessels show higher expression of angiogenic mediators when compared to normal conjunctiva in the absence of erythropoietin co-localization suggesting that Epo-independent EpoR- signaling pathway may also contribute towards the pathogenesis of pterygium. The expression of Ets-1 transcription factor, a proto-oncogene involved in vascular proliferation as well as matrix degradation is also upregulated in pterygium model. However there needs to be an exact understanding regarding how these mechanisms work in step- by-step manner in order to enable the development of potential therapeutic targets against pterygium in future.
It appears that angiogenesis is augmented by enhanced inflammation, and vice versa. An upregulation of mast cells show a positive correlation with blood vessel density within the pterygium body. Pterygeal epithelium as well as the substantia propria show aggregates of CD4 and CD 8 T lymphocytes which are absent in normal conjunctival specimen. Excised pterygeal specimens show significantly higher inflammatory cell count in proportion to the severity along with MMP1, MMP2 and MMP3 immunostaining. The infiltrating mononuclear cells secrete substance P which stimulate NK1 receptors on the pterygium epithelium to allow a radial growth pattern of pterygium cells. Other pro-inflammatory mediators are also increased in pterygeal tissue when compared to healthy autologous conjunctiva such as, fibronectin in the stroma, macrophage-inflammatory protein-4 (MIP-4) in all areas of pterygium, lipocalin 2 in the basal epithelial cells, while Per1 and Ephrin-A1 are decreased in pterygium.
Pterygium tissue shows abnormal hemo oxygenase –ferritin regulation, a system which governs the level of activity of eicosanoids in the body. Messenger RNA (mRNA) expression of constitutive HO isoform is upregulated by as much as 40%; that of CYP4B1 mRNA by 2-folds in pterygia compared with control tissue. Pro-inflammatory modulators are increased like lipoxygenase, CYP4B1-derived 12-HETE, prostaglandin E2 and thromboxane B2 and anti-inflammatory factors like hydroxyeicosatetraenoic (HETE) acid levels are reduced in pterygia compared with controls. Immunohistochemical studies on pterygium show an accentuated cyclooxygenase 2 (COX 2) immunostaining within the stromal CD68 positive macrophages when compared to normal conjunctiva, suggesting a plausible role of inflammatory mediators. This expression is much more in recurrent pterygium than in normal conjunctiva or in primary pterygium. Pterygium body fibroblasts also over-expressed insulin like growth factor binding protein 2. However enhanced expression of insulin growth factor 1 (IGF1), TGF B1and EGF on PCR amplification in the pterygium tissues was not seen. Nevertheless, an abnormal expression as well as response to the expressed proteins plays a key role in the progression of this lesion.
Stromal cell-derived factor 1 (SDF1) expression is increased in cases of severe pterygia. The interaction between SDF-1 and chemokine receptor 4 (CXCR4) may be responsible for the myofibroblast transformation of conjunctival cells. Levels of peroxiredoxin 2 are also increased in pterygeal tissue which may play a role in peroxidation of proteins and apoptosis. Higher levels of human cystatin C which is a potent inhibitor of lysosomal proteinases have been found in pterygium as well as tears confirming an upregulated inflammatory activity. Other than lymphocytic infiltration, these tissues also exhibit higher than normal positivity for endothelial cell adhesion molecules like ICAM-1 and VCAM-1; and HLA-DR.
 
Lymphangiogenesis
The growth of pterygium also appears to be stimulated by VEGF C expression which is specific for lymphatic vessels and is expressed by the pterygeal tissue in excess of the normal conjunctiva as determined immunohistochemically. Expression of VEGF C within the fibrovascular lesion stimulated the infiltration of (LYVE-1+) lymphatics within the tissue. An increased density of lymphatic vessels within the tissue is directly proportional to the severity of pterygium as well as with the expression of VEGF C. Lymphatic vessel area, density as well as luminal area positively correlate with the area and size of pterygium. Moreover, recurrent pterygium also show increased density of lymphatic microvessels suggesting a role of lymphangiogenesis in recurrence. However, recurrence is not significantly associated with grade of pterygium or when blood vessel (CD 31+) density is more than 20.
 
Tumorigenesis
Pterygium has long been considered to be a degenerative lesion. However, current evidence points towards pterygium 5being a preneoplastic lesion as it exhibits certain characteristics similar to tumor cells like proliferation, invasion and epithelial mesenchymal transition. In a histopathological study on 100 excised specimens of pterygia, 5% showed evidence of in situ ocular surface squamous neoplasia and 6 cases showed presence of primary acquired melanosis. Hirst reported the incidence of ocular surface squamous neoplasia (OSSN) to be 9.8% in nonsuspecting samples of pterygia. This suggests that the development of OSSN may be a continuum of spectrum in the disease process of pterygium.
The tested specimens from pterygium epithelium express higher tissue factor as well as epidermal growth factor receptor in contrast to normal conjunctival epithelium. Several epithelial cells show intense nuclear immunoreactivity for beta-catenin, E-cadherin as well as lymphoid-enhancer-factor-1, rendering them the property of inter-cell dissociation which is confirmed on transmission electron microscopy. The high expression of cellular proliferative markers like Ki 67 and proliferating cell nuclear antigen (PCNA) and anti-apoptotic factors like high Bcl 2 and mutant p53 indicate a high proliferation rate in combination with low apoptosis rate contributing to its pathogenesis. In addition to a loss of heterozygosity in p53 seen in approximately 40% of excised tissues, there is an increased expression of ‘survivin’ protein, resulting in a decreased apoptosis rate of pterygium cells.
The role of trefoil factor 1 (TFF 1) is also being investigated in preventing conjunctival cell apoptosis during the state of inflammation. Quantification of TFF1 mRNA shows that it is more strongly expressed by the pterygium cells than the normal conjunctival cells. Histopathology of pterygium epithelium shows it to be composed of multiple layers of round cells with goblet cells which are reactive for p27 with nuclear immunopositivity for cyclin D1 and Ki 67 suggesting epithelial cell hyperplasia. Active proliferation markers like K16, P63 and Ki67 are greatly increased in samples of pterygium compared to normal conjunctiva.
Newer molecules like angiogenin and aquaporins (1 and 3) which are seen to proliferate traditionally in tumor population are localized in the pterygeal tissue in greater quantity than normal conjunctiva. Further, levels of antitumor factor, microRNA-145 (miR-145) decrease with increasing severity of pterygia. Importin 13 has been recently diagnosed as a novel biomarker for corneal proliferating calls and it is co-localized with keratin 17 in basal cells of pterygium.
 
Genetics
Genetics may have a contributory role in the causation of pterygium as it has been reported to occur in families. A positive family history imparts the strongest and independent risk factor for the development of pterygium; the risk being maximum in those subjects with at least 3– 5 relatives affected with pterygium. Polymorphism in CYP1A1 gene (cytochrome P4501A1) is significantly increased within pterygeal tissue when compared with normal conjunctiva; suggesting that it may become a potential biomarker for pterygium. CYP1A1 is involved in the metabolism of polycyclic aromatic hydrocarbons (PAH); a mutation in this enzyme allows increased concentration of PAH, one of which is benzo[a]pyrene 7, 8-diol 9, 10-epoxide (BPDE). It binds with deoxyguanosine of DNA covalently and results in mutation of p53 by forming BPDE-like DNA adduct, the concentration of which is increased within pterygium in comparison with normal tissue.
 
Viruses and Other Infective Agents
Similar to the role played by UV radiations, human papilloma virus (HPV) induced p53 protein inactivation may be a factor in the pathogenesis of pterygium. HPV induced pterygium development seems to vary with changes in geography as well as ethnicity of population studied. HPV 1 and 2 are found in 58.3% of pterygeal tissues compared to the presence of HPV 16 in 9.5% of control specimens. Another study found 26% pterygeal tissues to be positive for HPV with 48.3% of these having HPV16/18 E6 oncoprotein incorporation on nested polymerase chain reaction (PCR). E6 oncoprotein binds with p53 tumor suppressor gene, and inhibits its action on apoptosis of dead and mutated cells. Amongst Danish population, HPV6 type was observed in 4.4% of pterygia, but none had in situ hybridization. Similarly, HPV was not recovered in any of the isolated specimens of pterygia amongst Chinese population in Taiwan, Japanese and Brazilians.
Other than HPV, investigators have also studied the plausible role of herpes simplex virus (HSV) and Epstein-Barr virus (EBV) in the causation of pterygium. Despite pterygeal specimens being positive for HSV, in situ DNA hybridization is negative. EBV is localized in 10% of primary pterygeal samples, thus playing a likely role in the pathogenesis of pterygium. Another study on pterygium samples in HIV infected patients found HPV positivity in 75%, kaposi sarcoma associated herpes virus (KSHV) in 50%, EBV in 88% and cytomegalovirus (CMV) in 60% on PCR amplification. In situ DNA hybridization analysis and immunohistochemistry further identified DNA integration of genome of HPV, EBV and KSHV in some of these samples, thus incriminating multiple oncogenic viruses in the causation of pterygia. Despite this evidence, ambiguity exists about the causative relationship of these viral agents with the development of pterygia. Longitudinal, multiethnic studies may shed more light on this area.
 
Others
Due to lack of clear understanding with regards to the pathogenesis of pterygium, certain other risk factors have also been identified in the causation of pterygium. A deficiency of essential trace elements like Cr, Mn, Zn and Se is observed in pterygium when compared to normal conjunctiva. Alteration in intracellular cholesterol metabolism within the pterygeal fibroblasts is also seen. Additionally expression of low density lipid (LDL) receptors makes them akin to tumor cells and amenable to verteporfin therapy, which is still investigational at 6this stage. Hence, an interplay of various co-factors contribute to the causation of pterygium.
 
Risk Factors
Liu et al in their meta-analysis of 20 population based studies on 900,545 subjects found the pooled prevalence rate of pterygium to be 10.2% (95% CI 6.3% to 16.1%). They found that variables such as male gender, increasing lattitude, age and outdoor activity have higher risk for pterygium world- wide. Studies conducted on populations native to South India, Norfalk island, rural Dali in China, Malays of Singapore, Japan and Spain report that there is a positive correlation between exposure to sunlight and presence of pterygium. There is an increased prevalence of higher grades of pterygia with sunlight exposure of more than 5 hours. Since majority of studies provide evidence for a positive association, sunlight plays a likely role in the etiopathogenesis of pterygium.
It is speculated that spectacle use may be protective against pterygium as the risk increases significantly in those not using glasses. A multitude of factors involving UVB radiations probably determine the final occurrence of pterygium which include time of the day, season, ambient UV radiation, geography, altitude and latitude, solar direction, environmental conditions like clouds which reflect and scatter light, individual anatomic factors like shape of nose, prominence of eyebrows, genetic factors and protective measures such as, use of hat with large brim and UV protective spectacles as seen in Chinese, Tibetan population. Further Kumejima study failed to prove any beneficial effect of hats, prescription glasses and sunglasses against pterygium whereas contact lens wear is found to be protective. It is believed that UV blocking contact lenses are better than spectacles as they also block the peripheral light from affecting the ocular surface unlike the spectacles.
 
Other Environmental Factors
Arc welding confers a higher risk of pterygium compared to carbide welding. 17.5% of welders had pterygium which is associated significantly with age as well as duration of occupation of the welders. Amongst other environmental factors, ocular mite infection by demodicosis has also been implicated in the pathogenesis of pterygium, more so for recurrent pterygium.
 
Smoking
Though smoking or tobacco consumption is not found to be a risk factor for development of pterygium by most studies, nonsmoking is associated with pterygium development in Koreans. Similarly, smoking is found to offer protection against pterygium development in Latinos inhabiting Arizona and in the Handan eye study. Hence the exact role of smoking or tobacco consumption in the development of pterygium remains unknown at present.
 
Age
Increasing age is found to be risk factor for pterygium in most studies.
 
Gender
Pterygium has been reported more frequently in men compared to women, probably because they are the outdoor working population. However few studies indicate that it occurs more frequently in women. One of the reasons provided for this discrepancy is that VEGF gene 460 shows polymorphism in females only, which predisposes them to the development of pterygium at an early age. In a study on multiethnic Asians staying in Singapore, male gender was associated with the risk of severe pterygium.
 
Race
Racial differences factors seem to affect the prevalence of pterygium in various populations. In a study conducted on multi-ethnic Asians living in Singapore, the prevalence in Malays is significantly higher than Chinese and Indians. The study concluded that since all the groups are living under similar environmental conditions, the racial differences could have accounted for the dissimilar prevalence. Significant difference in the prevalence of pterygium has also been observed amongst different races of Brazilian Indians dwelling in rain forests.
 
Socioeconomic Status, Area of Residence and Educational Status
Low socioeconomic status is associated with an increased prevalence of pterygium in studies on Latinos and Chinese Tibetans. Reports from varying geographical regions like South India, Korea, Beijing and Croatia show that the prevalence of pterygium is significantly higher amongst population living in rural areas. Low education level is a significant risk factor for pterygium in various studies. Thus, certain acquired environmental factors like low socioeconomic status, rural residence and low education may play a significant role in the causation of pterygium.
 
Outdoor Activity
A strong association between the amount of outdoor activity and the presence of pterygium is reported in various studies. Outdoor activity is also associated with severe pterygium. The Kumejima Study found a positive association between occupation such as fishing and farming and pterygium whereas service industry and office work are protective against pterygium.
 
Systemic Risk Factors
  • Hypertension: High blood pressure is found to be a significant risk factor in Singapore Malay study. The Kumejima 7study found a significant asssociation with high systolic blood pressure, not seen with high diastolic blood pressure, but the positive relationship could not be proved by others.
  • Diabetes: Two studies looked into the association of diabetes with pterygium and could not find any causative relationship between the two.
  • Cholesterol levels: A higher odd's ratio of presence of fleshy pterygium with increased serum total cholesterol levels is identified in few studies.
  • Height and weight: The Kumejima study found a positive inter-relationship between greater height and lesser weight in those subjects with pterygia compared to the healthy population. However, the clinical relevance of this information is not clear at the present moment.
 
Ocular Factors
  • Dry eyes: Dry eyes lead to a chronically irritated ocular surface, prevent the wash-out of toxins from the eyes, and have been implicated in the initiation of pterygium. Evidently, decreased tear breakup time is a risk factor for pterygium development in studies conducted on Chinese Mongolians and Chinese Tibetan inhabitants.
  • Skin and iris pigmentation: Skin phenotype that tans compared to burning of the skin when exposed to sunlight is associated with a higher incidence of pterygium in one or both eyes. No correlation exists between the intensity of iris hyperpigmentation and pterygium development in native Spanish population.
  • Refractive error: There are conflicting reports suggesting the plausible role of refractive error in development of pterygium. Beijing eye study could not find any association of pterygium with type of refractive error. On the other hand, the Kumejima study found a positive correlation between pterygium and hyperopia.
  • Intraocular pressure: Low intraocular pressure is observed to be an independent risk factor in the causation of pterygium. Though exact mechanism for this occurrence is not known, IOP measurement in eyes with pterygium is influenced due to changes in ocular rigidity and hysteresis.
  • Vertical interpalpebral fissure distance and ocular protrusion: Though UV light is strongly implicated in the pathogenesis of pterygium, ocular morphological variations like ocular protrusion and vertical interpalpebral distance which might change the level of exposure to these radiations in different individuals did not show any positive correlation with the causation of pterygium.
 
Conclusions
Hence, the development and progression of a seemingly innocuous lesion like pterygium is influenced by multiple independent risk factors. The final pathway leading to its pathogenesis is complex and is being understood. Host of different factors continue to be added in the current gamut as our understanding pertaining to its pathogenesis continues to evolve.
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