In recent years, we observed an increase in the incidence of pterygium, both primary and recurrent. Thus, we decided to write this article and make a review of the physiopathology of this process to establish guidelines in order to improve its treatment.
Pterygium is a benign neoplastic lesion, characterized by local invasive fibrovascular growth of the conjunctiva to the cornea (1), as shown in Figure 1.The origin of this tissue proliferation is derived from the basal epithelial stem cells of the limbal bed (LESC), that are activated and transformed into conjunctival tissue (2).It is thought that the main trigger factor is the ultraviolet-light radiation, therefore the incidence is much higher in equatorial countries, with high rates of insolation (3-6). It does not appear that there is a genetic predisposition to pterygium, although some research have suggested it (7).
The ultraviolet radiation would act on the temporal eye’s area, spreading throughout the cornea, as if it were a double mirror formed by the epithelium and endothelium, and reaching the nasal side (Figure 2), with a predominant effect of up to 20 times higher in the way out (nasal side) with regard to the way in (temporal side) (8). Then, the injury begins at the nasal side, which it is more protected from the sunlight, even though it seems a contradiction.
The first UV light effect on the tissues is an elastic degeneration of the own subconjunctival substance. The UV light activates fibroblasts that generate abnormal elastin and can not be degraded by elastase (9,10). The abnormal elastin will accrue to give an image of rounded injury, like a yellowish bump, located in the nasal area, next to the limbus, that is better known as Pinguecula. (Figure 3). Alongside this degenerative process, another degenerative inflammatory reaction is also associated, responsible for the development of blood vessels in the subconjunctival space, surrounding the lesion and forming a fibrovascular triangular-shaped growth with vertex towards the cornea, which will turn into Pterygium.
Histochemical studies and molecular biology show that in the pterygium, the LESC (Limbal Epithelial Stem Cells) express a mutated tumour suppressor gene that causes the presence of protein p53 (11,12), a common marker in various human cancers and in lesions of actinic skin (13), which suggests that pterygium would be a proliferative disorder similar to a tumour. The p53 gen is associated with programmed death cell mechanisms.
The UV light act on the LESC causing mutation in the gene responsible for the p53 protein synthesis, the gene loses its ability to act as a transcription factor, resulting in uncontrolled cell proliferation and a change to the signals that activate growth factors and the cyclins D1-Cdk4 (11,12). The implications of the p53 gene mutation is that LESC grow uncontrolled (14), migrate and grow onto the cornea through the basal membrane (15), dragging along conjunctival cells and inducing the formation of fibrovascular tissue at this level, due to increased levels of inflammatory mediators, proliferative and angiogenic factors, such as found in the histopathologic and histochemical analysis (16).
These studies reveal, in turn, that changes occur mainly in the “head” of the pterygium, the area that moves onto the cornea, and much less in the rest of the lesion. This is a crucial data when treating pterygium surgically: the complete head must be carefully removed in order to completely eliminate the mediators responsible for the progress of pterygium, causing frequent recurrence after surgery.
When fibrovascular tissue reaches the cornea, the balance between the matrix metalloproteinases (MMPs) and the inhibitors of these enzymes breaks, the MMPs (17) concentration increases, especially in pterygium’s head, inducing changes in the collagen structure of the basal membrane of the corneal epithelium, the Bowmann and corneal stroma. Also, a weakening of the collagenous structure occurs, leading to the penetration of the fribrovascular tissue from the limbus towards the cornea (18). Once the barrier of the cornea is weakened, the progression of the fibrovascular tissue occurs by the presence of inflammatory factors, cytokines and pro-angiogenic factors (especially the presence of VEGF), and growth factors of fibroblast (particularly TGF-Beta). Their identification opens a new pathway to treatment of pterygium.
In summary, UV radiation and micro trauma lead to a chronic inflammatory process, with function loss of the natural barrier of the corneal conjunctival limbus. Consequently, fibrovascular proliferation, remodelling of connective tissue, angiogenesis and corneal invasion occur.
The standard treatment is surgery: the pterygium is removed with special attention to the corneal region where the pterygium’s head is located. After the removal, if it is of small size, the procedure is concluded after suturing the edges of the healthy conjunctiva. Yet, if it is of big size and/or of recurrent type, a graft of conjunctiva, of amniotic membrane or of cultured stem cells is needed.
This procedure is effective in a high degree of cases but there are still a high percentage of relapses that require further surgery. It is unclear the cause of relapses but everything suggests that there is still some degree of inflammatory reaction and a limbus condition that facilitates the new fibrovascular proliferation and corneal invasion, as well as the persistence of the casual factor, the UV radiation; for it is necessary to take these three factors much into account.
1.- Protection against ultraviolet radiation.
First, it is obvious that we must protect the eyes from the UV light. Hence, we shall stress to the patients to avoid this type of radiation, either by reducing their exposure to sunlight or using good quality wrap-around sunglasses that have the right UV filter.
2.- Inhibition of the local inflammatory reaction.
As for the second factor, the inflammatory reaction, it is necessary to take pre-operative, intraoperative and postoperative measures. Prior to the surgery, it is important to administer anti-inflammatory drugs, that is, topical steroids or previous infiltration of anti-VEGF. Good results in this sense have been reported, both for the incidence of recurrence as for the recovery after surgery. At an intraoperative level, it is advisable to apply drugs that inhibit fibroblast proliferation, such as Mitomycin C. Studies show the effectiveness of this drug, its application to 0.02 % for 30 sec. shows very good results (19). Other drugs, such as Thiotepa or 5-Fluorouracil (20) have not proven the same level of effectiveness.
In the postoperative period, it is also necessary to control inflammation, especially in the early stages, thus it is indispensable to administer topical steroids. It has even been proposed the instillation of Mitomycin C as eye drops in complex cases, where recurrence would likely happen. Perhaps today the most recommended step in preventing recurrence (or when it has hardly started) would be the VEGF inhivitors infiltration in the danger zone (21).
3.- Selective surgery and reconstruction of the conjunctiva.
The third factor, the prevention of recurrent corneal invasion, involves taking a series of surgical measures. The surgical technique must be careful, by shearing off all the triangular-shaped pterygium (head and body). The body is composed by an abnormal growth of conjunctival epithelium and a connective fibrovascular tissue that need to be removed completely.
The head of the pterygium must be dissected from the underlying cornea, reaching out its deeper layers and removing it entirely. It is essential that the corneal and limbic surface be regular and smooth, otherwise the fibrovascular tissue of the conjunctiva will grow back, starting the risk of recurrence. To achieve this goal, certain special instruments that help “polishing” the surface are required, such as a diamond drill powder or the Barraquer Aero Rotor.
Once the abnormal tissue is removed, the possibility of suturing the edges of the healthy conjunctiva must be considered. If possible, non-inflammatory sutures must be used, like nylon, since vicryl being of resorbable type (more commonly used) might encourage fibrovascular re-growth. When the denuded area cannot be occluded by approximating the conjunctiva’s edges, it is necessary the use a graft as a barrier to recurrence. If possible, it is also better to use a conjunctival graft of the same eye, taken from the superior bulbar conjunctiva. Had it not enough tissue in the eye, the contralateral eye’s tissue may be used, taking special care of getting healthy limbal cells to ensure the regeneration of the area.
Another option is the implantation of ex vivo culture stem cells on amniotic membrane support (22). The graft may be sutured or fixed through adherent substances such as fibrin (Tissucol TM).
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