Different techniques for pterygium surgery Technique Advantages Disadvantages Authors’ personal experience Simple excision with bare sclera Easy High recurrence rate We do not perform this technique due to high rate of recurrence Simple excision with primary closure Easy Less postoperative pain compared to first technique High recurrence rate We don’t perform this technique due to high rate of recurrence Mitomycin C Decreased recurrence rate Higher concentrations have many complications Mitomycin C 0.02% is effective with minimal complications Cyclosporine Reported to decrease recurrence rate Many complications No role in pterygium surgery Bevacizumab Reported to decrease recurrence rate Not effective for preventing recurrence Inhibit fibrovascular tissue proliferation more than decreasing recurrence rate β-Irradiation Reported to decrease recurrence rate Significant complications Abandoned nowadays due to problems in its availability and teratogenicity Conjunctival autograft and limbal conjunctival autograft Decreased recurrence rate Good cosmetic appearance Time consuming Interfere with glaucoma surgery if needed later Good and effective technique with satisfying results Amniotic membrane grafting Decreased recurrence rate If fresh, may transmit infection Difficult preservation in developing world Results of this technique are not encouraging Mini-SLET Decreased recurrence rate Time consuming Recommended if autograft is not possible Tailored corneo-conjunctival autografting Has lowest recurrence rate reported Time consuming Lowest recurrence rate reported No major complications Better cosmetic appearance Subconjunctival excision More anatomical excision (the conjunctiva is not involved in pterygium but the Tenon’s capsule) Better wound healing, less scarring, and less recurrence rate No long-term studies Low recurrence rate Better wound healing and less scarring Fast surgery Minimally invasive Abbreviation: Mini-SLET, minor ipsilateral simple limbal epithelial transplantation. Simple excision was the first surgical treatment prescribed for pterygium leaving bare sclera, but was associated with high recurrence rate ranging from 40 to 70%. 5,6 It was first described in 1948. 7 To prevent recurrence, adjunctive therapies are to be considered. These include application of antimetabolites, such as MMC, radiotherapy, conjunctival or limbal conjunctival autograft, 8 and AM graft. Primary closure is a technique that involves excision of the pterygium, followed by suturing of the remaining conjunctiva on either side of the wound over the bare sclera, to close the defect. This procedure has also been reported to have an unacceptably high rate of recurrence (45–70%) compared to newer techniques. 9 MMC is an alkylating agent, which inhibits deoxyribonucleic acid (DNA) synthesis. By inhibiting DNA synthesis, it leads to the death of cells caused by the inability to repair the genotoxic injury due to alkylation. It acts against all cells regardless of the cell cycle and even acts in cells that are not synthesizing DNA. Inhibition of DNA synthesis leads to reduction in the number of mitoses, especially when MMC comes into contact with cells that are in the late G1 and early S phases of the cell cycle. It can be used before, during, or after pterygium surgery by applying locally or in the form of eye drops. The injection application directly on the pterygium has the advantage of protecting the corneal endothelium and epithelium. Subconjunctival injection allows a more precise dose to be applied to the patient’s eye, which usually does not occur with MMC application while using sponges directly on the sclera during surgery. Its action in the prevention of pterygium recurrence occurs by inhibition of fibroblast proliferation in the episcleral region. The increased concentration and duration of the application may be associated with complications such as necrotizing scleritis, scleral calcification, ulceration, corneal edema, iritis, glaucoma, cataract, hypotony by injury of the ciliary body, and damage to the corneal epithelium and endothelium. 10,11,12 The administration of MMC in the pterygium surgery is considered off-label by the Food and Drug Administration (FDA), but it is used in cancer treatment. Twenty-two trials 9,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 that used MMC in different concentrations (0.002–0.4% for 3–5 min) applied to the bare sclera after pterygium excision were evaluated. Some studies with primary pterygium determined that all MMC concentrations, from 0.002 to 0.04%, given for 3 to 5 minutes, significantly reduced (< 0.0045) the recurrence of pterygium when compared to excision with bare sclera. 9,14,16,19 The recurrence rate reported in the literature for intraoperative use of MMC in primary pterygium surgery varies from 6.7 to 22.5%. 33,34 The most common dose, according to the literature, is 0.02% for 3 minutes in the bare sclera. 35 Complications related to the intraoperative use of MMC vary according to the concentration and the duration of application. With the most commonly used dose of 0.02% for 3 minutes, there were no severe complications reported. 35 Delayed epithelialization can occur with the use of intraoperative MMC 0.04% for 3 to 5 minutes, but it was not reported with MMC 0.02% for 3 minutes. Iritis and corneal dellen have been reported in 3% of cases when MMC 0.01% was used for 5 minutes intraoperatively. 14 The analysis included 12 trials 17,18,19,23,26,27,28,29,32,36,37,38 with application of different concentrations of MMC after surgery at different times. In two studies with MMC application postoperatively (0.02% twice a day for 5 days), there was reduced primary pterygium recurrence. 23,26 High concentrations of MMC (0.04%, 3 to 4 times daily for 7 days) result in a significant reduction in the recurrence of pterygium compared to excision with bare sclera. 38 Studies with primary pterygium 24,27 or combined with recurrent pterygium 26,28 reported no significant changes, comparing the intraoperative or postoperative use of MMC. Sclera ulceration occurred in a proportion that varied from 5 to 19% in eyes with postoperative MMC 0.02% applied twice daily for 5 days, 17 with MMC 0.02% applied 4 times daily for 7 days 24 and 0.04% applied 3 times daily for 7 days. 28 Iritis and corneal dellen occurred with postoperative use of MMC 0.02% 4 times daily for 7 days in 3% of the cases. 28 Two studies 14,18 have shown increased risk of scleral thinning with increasing concentration of MMC application. The preoperative subconjunctival injection of MMC, in a study of 25 eyes, proved to be efficient, with two cases of delayed epithelialization. Ninety-two percent of eyes with MMC application experienced no recurrence, and 8% had a 2-week delay in corneal epithelialization. No serious complications were reported. 39 Donnenfeld et al reported the efficiency and safety of using preoperative MMC injection of 0.1 mL (0.15 mg/mL) in the pterygium body 1 month prior to the surgery for pterygium recurrence. The results showed less vascularization and inflammation within the pterygium 1 month after injection of MMC with a 6% recurrence after 2 years of follow-up. 40 The risk of preoperative injection is due to the impossibility of washing the MMC that is in the subconjunctival space and can generate toxicity. Studies showed that subconjunctival injection of MMC 0.2 mL (0.4 mg/mL) injected 2 mm posterior to the limbus caused cell changes, such as flattening and pyknotic nuclei in the ciliary body epithelium, leading to reduction of aqueous humor production a month after the injection. 41 Our personal results with this technique are very good without reported complications. We use MMC preoperatively in the preparation of surgery for reoperations. Four weeks before the surgery, we inject 0.2 cc of MMC, 0.02% subconjunctivally. Then the surgery is performed as usual (we only perform subconjunctival excision of the pterygium respecting the conjunctiva and without conjunctival flap transposition). In over 100 cases, we have not observed any complication, and our recurrence rate is 2%. This technique is time saving and is very effective in our hands. Cyclosporine is an immunosuppressant that selectively suppresses T-helper cells, controls interleukin synthesis and secretion, and inhibits vascular endothelial growth factor (VEGF). 42 Topical cyclosporine is relatively effective in inhibiting pterygium recurrence, but topical cyclosporine causes minor complications, such as irritation, hyperemia, and rarely, scleromalacia. 43 Turan-Vural et al 44 divided 36 eyes (34 patients) with primary pterygium into two groups and reported that the rate of recurrence was 44.4% in the group that received pterygium surgery using the bare sclera method alone, but was 22.2% in the group receiving postoperative instillation of 0.05% cyclosporine. The cyclosporine-treated group showed no adverse reaction other than a mild burning sensation and irritation upon application. For 31 patients (62 eyes) diagnosed with bilateral pterygium, Yalcin Tok et al 45 instilled 0.05% cyclosporine in the right eye, using the left eye as a control, and reported a rate of recurrence of 12.9% in the right eye and 45.2% in the left eye, which indicated that cyclosporine was effective in reducing pterygium recurrence. Nowadays, there is no role of cyclosporine in pterygium surgery. Bevacizumab is an anti-VEGF antibody that inhibits angiogenesis and has been studied as an adjuvant therapy to inhibit post-surgery pterygium recurrence. 46 Bevacizumab, a recombinant human monoclonal antibody, is an inhibitor that binds to all biologically active forms of VEGF. In 2004, the FDA approved the drug for the treatment of metastatic colorectal cancer. In addition, bevacizumab showed promising results in ophthalmology for the treatment of many diseases related to angiogenesis, such as macular degeneration-related choroidal neovascularization, proliferative diabetic retinopathy, and retinal vein occlusion. 47,48 Bevacizumab can cause severe systemic problems, such as endophthalmitis and arterial thromboembolic events. 49,50 Motarjemizadeh et al 51 enrolled 90 patients (90 eyes) who underwent pterygium excision and categorized them into three groups. At 24 hours after surgery, group II and group III received a 5 and 10 mg/mL dose of topical bevacizumab, respectively, whereas patients in group I were administered only a placebo starting 1 day after surgery. Participants were instructed to instill their topical medicines four times a day for 1 week. These authors concluded that 10 mg/mL of topical bevacizumab was more efficacious than 5 mg/mL in preventing pterygium recurrence. Ozgurhan et al 46 divided 44 patients (44 eyes) who underwent excision of recurrent pterygium with conjunctival autograft into two groups, one of which was instilled with bevacizumab four times a day for a month, starting 1 month after surgery. Bevacizumab failed to reduce recurrence, but effectively inhibited angiogenesis. Suh and Choi 52 divided 54 patients (54 eyes) who underwent primary pterygium surgical excision into two groups and, after administering subconjunctival bevacizumab injections to one group, reported that it failed to affect recurrence, but successfully inhibited proliferation of fibrovascular tissues. β-irradiation has also been found to be a relatively well-tolerated procedure, with recurrence rates similar to chemotherapeutic agents and conjunctival autografting. Rare but significant complications of this procedure include scleral thinning, ulceration, infection, and radiation-induced cataract. 53 This type of therapy is abandoned nowadays due to problems in its availability and teratogenicity. In conjunctival autograft surgery, conjunctival tissue from another part of the person’s eye along with limbal tissue is resected in one piece and is used to cover the area from which the pterygium was excised. There is widespread acceptance of conjunctival autografting and application to pterygium by Vastine et al and Kenyon et al. 8 However, no single autograft technique is completely effective in preventing recurrence. Pterygium excision followed by conjunctival autograft is associated with recurrence rate of 5.3 to 39%. 8 After the initial report by Kenyon et al, describing the success of conjunctival autografting following pterygium excision, other authors have largely failed to achieve the same success rate. 6,8 The wide range of recurrence rates reported number of factors. Review of published literature suggests that the surgical technique could probably be the single most important factor influencing recurrence. The meticulousness with which the limbal tissue is included in the autograft, in our opinion, determines the success of the procedure. Various studies have specifically described the inclusion of limbal tissue in the graft and have demonstrated low recurrence rates. 8,54 Limbal autografts have been used successfully to correct limbal dysfunction, acting as a barrier against conjunctival invasion of the cornea and supplying stem cells of the corneal epithelium. The importance of limbal transplantation in ensuring low recurrence rates has also been stressed by Figueiredo et al. 55 A major drawback for limbal conjunctival autograft transplantation is that it is technically more demanding and time consuming. AM being a basement membrane acts as a new healthy substrate suitable for proper epithelization. It has a strong anti-adhesive effect 56 being normally avascular and thus it inhibits the incursion of new vessels. 57 AM grafts are thought to promote healing and reduce rates of recurrence because of their anti-inflammatory properties, their promotion of epithelial growth, and their suppression of transforming growth factor β (TGF- β) signaling and fibroblast proliferation. 9 In the 1940s, AM use in the treatment of ocular surface conditions was described. 57 Since 1995, it has been increasingly used to treat a variety of ocular surface conditions, 58 including persistent corneal epithelial defects, acute chemical burns, and cicatrizing conditions, such as Stevens–Johnson syndrome and ocular cicatricial pemphigoid. 58 Amniotic membrane transplantation (AMT) has been used in the reconstruction of fornices, as a covering following excision of conjunctival lesions, and in limbal stem cell deficiency with concomitant limbal stem cell grafting. 58 AM can be prepared fresh or preserved using either freeze-drying of the membrane (dry AM) or cryopreservation. Fresh AM is more commonly used in the developing world, where preservation techniques are not easily performed. 59 Unfortunately, the use of fresh AM is less advantageous, not only because it must be used in a limited time and does not exploit the size of the membrane for multiple tissue transplantations, but it also poses a greater risk of transmitting infection. 59 Cryopreservation of AM is achieved by freezing fresh AM in either phosphate-buffered saline in dimethyl sulfoxide or in Eagle’s Minimum Essential Medium (MEM) with glycerol, both at –80°C. 59 Recurrence rates of pterygia following amniotic membrane grafting (AMG) are cited between 14.5 and 27.3%. 9 Reported complications include wound dehiscence, Tenon’s granuloma, conjunctival cysts, necrotizing scleritis, and subconjunctival fibrosis from the donor site. 60 Our personal experience with this technique is not good and results were not encouraging. AM graft to cover the bare sclera area is combined with a small autologous simple limbal epithelial transplant (mini-SLET) to provide stem cells at the limbal area. 61 Mini-SLET is recommended for pterygium in cases that are not good candidates for a conjunctival autograft. A tailored corneo-conjunctival graft was prepared from the superior side with the same size of the bared sclera sparing the deep Tenon at the donor bed in the conjunctival part for rapid spontaneous healing without scar, and a crescent knife was used to dissect about 3 mm from the upper cornea with nearly the same thickness as conjunctiva to be included in the graft 62 (▶ Fig. 4.1). Tailored corneo-conjunctival graft offers the advantage of preventing recurrence in addition to better cosmetic appearance of the tailored graft (▶ Fig. 4.2). Fig. 4.1 Surgical steps of tailored corneo-conjunctival autografting: (a) traction suture, (b) dissection of the conjunctiva, (c) hooking the pterygium, (d) dissection of the pterygium from posterior to anterior and peeling the corneal part of the pterygium, (e) preparing the corneo-conjunctival graft, and (f) securing the graft with continuous nylon 10/0 suture.
4.2 Simple Excision with Bare Sclera
4.3 Simple Excision with Primary Closure
4.4 Mitomycin C
4.4.1 Mitomycin C during the Surgery
4.4.2 Mitomycin C after the Surgery
4.4.3 Mitomycin C before the Surgery
4.5 Cyclosporine
4.6 Bevacizumab
4.7 β-Irradiation
4.8 Conjunctival Autograft and Limbal Conjunctival Autograft
4.8.1 Amniotic Membrane Grafting
4.8.2 Minor Ipsilateral Simple Limbal Epithelial Transplantation
4.8.3 Tailored Corneo-Conjunctival Autografting
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