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Preoperative Subpterygeal Injection Vs Intraoperative Mitomycin C for Pterygium Removal: Comparison of Results and Complications
Preoperative Subpterygeal Injection Vs Intraoperative Mitomycin C for Pterygium Removal: Comparison of Results and Complications HAMID KHAKSHOOR, MOHAMMAD ETEZAD RAZAVI, RAMIN DANESHVAR, MOHAMMAD TAGHI SHAKERI, MAJID FARROKH GHATE, AND HALEH GHOOSHKHANEHI ● PURPOSE:
To evaluate and compare the recurrence rates and complications between 2 therapeutic methods for primary pterygium: subconjunctival injection of mitomycin C (MMC) 1 month before bare scleral excision and conjunctival rotational flap with intraoperative MMC use. ● DESIGN: Prospective, interventional, randomized clinical trial. ● METHODS: SETTING: Institutional clinical trial in a tertiary, specialty eye hospital. STUDY POPULATION AND INTERVENTION: We included 82 eyes diagnosed with primary pterygium and randomly allocated them into 2 groups. Group A consisted of 36 eyes treated with subconjunctival injection of 0.02% MMC 1 month before bare scleral excision, and group B comprised 46 eyes that underwent conjunctival rotational flap with intraoperative 0.02% MMC for 2 minutes. Follow-up periods were at least 12 months (range, 12 to 18 months). MAIN OUTCOME MEASURE: Recurrence and complication rate in each arm of study. ● RESULTS: During the 1-year follow-up, 2 cases of clinical recurrence in third and sixth month of follow-up occurred in group B (recurrence rate, 4.3%). In group A, there was no clinically significant recurrence, but 2 cases of hypovascularity and whitening of sclera at the site of pterygium excision was observed. There was no other serious complication. There was no statistically significant difference between groups for recurrence rate, mean age, sex, or pterygium area. ● CONCLUSIONS: Subconjunctival injection of MMC 0.02% (0.1 ml of 0.02% solution) 1 month before bare scleral excision is a quick, easy, and safe surgical procedure and is at least as effective as conjunctival rotational flap with intraoperative MMC for 2 minutes. (Am J Ophthalmol 2010;150:193–198. © 2010 by Elsevier Inc. All rights reserved.)
Accepted for publication Mar 24, 2010. From the Khatam Anbia Eye Hospital, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (H.K., M.E.R., R.D., M.F.G., H.G.); and the Department of Biostatistics and Social Sciences, Ghaem General Hospital, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (M.T.S.). Inquiries to Ramin Daneshvar, Khatam Anbia Eye Hospital, Ghareni Boulevard, Mashhad 91959-61151, Iran; e-mail: [email protected] 0002-9394/$36.00 doi:10.1016/j.ajo.2010.03.006
©
2010 BY
P
TERYGIUM IS A FIBROVASCULAR OVERGROWTH OF
conjunctival tissue encroaching on the cornea from limbus toward the center that resembles an insect wing.1 Overall prevalence of the disease is 5% to 15% and increases in tropical areas, which may suggest the pivotal role of ultraviolet (UV) light as the cause of the disease.2 UV exposure is widely accepted to be the single most important etiologic factor in pterygium pathogenesis.3 UV light may produce damage to the cellular DNA, RNA, and extracellular matrix4 and may induce expression of cytokines and growth factors important in the development of pterygium.5–7 However, the exact pathogenesis of pterygium remains uncertain. Other mechanisms have been proposed, including the role of cellular immunity through pathways involving cyclooxygenase-28,9 and matrix metalloproteinases.10,11 Another proposed mechanism focuses on the role of vascular proliferation in the development of pterygium.12,13 Generally, pterygium can be considered a proliferative, invasive lesion with focal limbal breakdown associated with excessive UV exposure. There are several indications for pterygium excision, such as decreased visual acuity resulting from visual axis involvement, tear film break-up, and/or irregular eye movement limitation; eye irritation and discomfort; inability to wear contact lenses; difficulty in performing refractive surgery; uncertainty about the diagnosis; and cosmetic concerns.14 Many different surgical techniques have been tried for pterygium removal with variable success rates. The most convenient technique is simple excision of pterygium. However, bare sclera technique of pterygium excision without adjuvant therapies (chemotherapy and radiation) has recurrence rates of 29.7% to 88.9%.15,16 In different studies, the adjuvant therapy with different concentrations (0.01% to 0.4%) of mitomycin C (MMC) has been associated with a 2.7% to 42.9% decrease in recurrence rate.17–19 Concerns about the sight-threatening side effects of adjuvant therapy have made alternative therapeutic measures as a popular research topic. In an attempt to decrease ocular surface exposure to intraoperative antimetabolites, subconjunctival injection of MMC has been proposed with a recurrence rate of 6%.20 Recently, combination of intraoperative MMC and rotational conjunctival flap has been reported as a highly efficacious treatment for
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FIGURE 1. Photograph showing estimation of pterygium surface on cornea. (Left) Pterygium height, h, and base, b, over the cornea are measured, and the surface area, a, is approximated as a ⴝ bh/2. In this patient, approximate area is 7.56 ⴛ 5.90/2 ⴝ 22.30 mm2. (Right) Actual surface area as calculated by software (22.78 mm2).
pterygium, with a reported recurrence rate of 3%.21 However, differences in patient inclusion criteria and the noncomparative nature of these studies have made conclusive decisions about the choice procedure difficult, if not impossible. The purpose of this study was to compare the 2 recently introduced surgical approaches (i.e., preoperative subpterygeal MMC injection with later bare sclera excision and intraoperative MMC application with conjunctival rotational flap) in terms of complications and recurrence rates.
checked the precision of the method with the Measuring Tool of Adobe Acrobat software (version 9 Pro Extended; Adobe System Incorporated, Burlington, New Jersey, USA). As evident in Figure 1, the surface area calculated with the equation is in close approximation to the actual surface area calculated by the software. All of the operations were performed by 2 of the authors (H.K. and M.E.R.), both skillful in pterygium surgery with a surgical experience of more than 15 years. In group A, the surgery was performed in 2 stages: in the first, officebased stage, the conjunctiva was anesthetized with instillation of tetracaine eye drops followed by local injection of lidocaine 2%. After waiting for 5 minutes to achieve sufficient anesthesia, and under the slit-lamp viewing, 0.1 mL 0.02% MMC solution (Mitomycin-C Kyowa; Kyowa Hakko Kogyo Co, Ltd, Tokyo, Japan) was injected sublesionally via a 30-gauge insulin syringe and along the limbus at the site of pterygium overgrowth over the cornea. A cotton-tip applicator then was used to compress the needle entry site to prevent MMC egress on the ocular surface. In the end, and in a recombinant position, the eye was irrigated copiously with at least 30 mL balanced salt solution. After injection, all patients received 0.5% chloramphenicol (Sina Darou, Tehran, Iran) and 0.1% betamethasone (Sina Darou) eye drops every 6 hours for 1 week. Follow-up visits were scheduled for 1 day, 1 week, and 1 month later. In the second stage, 1 month after the initial injection, bare scleral excision of pterygium was performed, as has been described previously.20 The eye was pressure patched and topical medications were restarted at the first postoperative day. At the second postoperative visit 1 week later, chloramphenicol eye drop was discontinued and betamethasone was substituted with topical 0.1% fluorometholone (Fluocort; Sina Darou) every 6 hours for 1 month. In group B, with a modified Pico technique,22 the patients underwent pterygium excision after local anesthe-
METHODS THIS WAS A RANDOMIZED CLINICAL TRIAL CONDUCTED ON
all eligible patients referred with a diagnosis of primary pterygium to a tertiary referral eye hospital in northeastern Iran (Khatam Anbia Eye Hospital) from October 2007 through June 2009. Pregnant or breast-feeding women and patients with a history of previous ocular surgeries; ocular diseases such as glaucoma, herpetic keratitis, and trachoma; or any autoimmune disease were excluded. Patients were allocated randomly into 2 groups. Randomization was carried out using envelopes containing random digits. Group A patients (envelopes with odd digits) underwent subconjunctival injection of 0.02% MMC 1 month before bare scleral excision. Group B patients (envelopes with even digits) underwent conjunctival excision with a rotational flap from the superior conjunctiva and intraoperative 0.02% MMC. A comprehensive ophthalmic examination, including best-corrected visual acuity testing, slit-lamp examination, Goldmann applanation tonometry, and fundus examination, was carried out for all participants. Assuming a pterygium to have a triangular shape, corneal surface area covered by pterygium, a, was estimated by multiplying maximum width, b, at pterygium base to half of its length, h: a ⫽ bh/2. We found this approximation to be a user-friendly approach with acceptable accuracy. We 194
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sia with topical tetracaine and local subconjunctival injection of lidocaine 2%. Pterygium was grasped at the limbus and avulsed from corneal surface with a muscle hook. A Wescott scissors was used to remove the pterygium body, and the corneal and sclera surfaces were polished with a no. 15 Bard-Parker blade. Minimal cautery was performed to control bleeding, and 0.02% MMC solution was applied to the bared scleral bed for 2 minutes, followed by copious irrigation of the ocular surface with at least 30 mL balanced salt solution. After releasing the superior conjunctiva, a conjunctival flap was rotated and fixed over the bare sclera using 8-0 Vicryl (Surgicryl; SMI AG, Hünningen, Belgium) stitches to cover the resection site, except a 2-mm zone adjacent to the limbus. Finally, topical ointments of erythromycin and hydrocortisone were applied and the eye was pressure patched. On the first postoperative day, 0.5% chloramphenicol and 0.1% betamethasone eye drops were administered every 6 hours for 1 week. The patients were visited 1 week later, and fluorometholone eye drops were administered (every 6 hours for 1 month) instead of betamethasone. If not degraded, the Vicryl sutures were removed at the third postoperative week. In both groups, follow-up visits were scheduled 1, 3, 6, 9, and 12 months after surgery, and a complete set of ophthalmic examinations was repeated with special focus on probable complications such as dellen formation, persistent corneal epithelial defect, recurrence, and scleral necrosis. After surgery, an overgrowth of fibrovascular tissue over the corneal surface of more than 1.0 mm was considered a recurrence, as has been described previously.20 One of the authors (M.F.G.), blinded about the study groups, performed all ophthalmic examinations; however, because of apparent differences between the ocular surface appearance of the study groups, especially in the early phase, there was practical limitation to the blinding procedure at the postoperative first month visit. In patients with bilateral pterygium requiring surgical intervention, a similar procedure was performed on both eyes; however, only 1 eye per subject was included randomly in the final analysis. Patients without regular follow-up were omitted from the study. Because some of participants were Afghani refugees, recruitment for follow-up examination was impossible after the first postoperative visits. We could assume that they had no major complication or recurrence; however, to be precise, we did not include them in the final analysis. The complication rate was compared between the 2 groups using chi-square and Fisher exact tests. Intergroup changes for continuous parametric variables were evaluated by the unpaired Student t test. All statistical analyses was performed with SPSS version 15 (SPSS Science Inc, Chicago, Illinois, USA). For all measurements, a 2-tailed test was used, and the statistical significance level was set at P ⬍ .05. VOL. 150, NO. 2
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FIGURE 2. Photograph showing whitening of sclera after pterygium surgery with preoperative subconjunctival injection of mitomycin C and subsequent bare sclera technique.
RESULTS EIGHTY-TWO EYES OF 82 PATIENTS WERE ENROLLED IN THE
study, including 36 eyes in group A and 46 eyes in group B. Initially, group A comprised of 66 eyes; however, 18 eyes were excluded because of incomplete follow-up and 12 eyes were omitted randomly in bilateral cases, leaving 36 eyes of 36 patients for the final analysis. Group B included 51 patients; however, 7 eyes of 5 patients with incomplete follow-up visits and 4 randomly selected eyes in bilateral cases were excluded from the final analysis. Finally, 46 eyes of 46 patients were evaluated in group B. There were 18 (50%) and 24 (52.2%) females in groups A and B, respectively (P ⫽ .840). The mean age of all patients was 48.48 ⫾ 13.67 years (range, 20 to 80 years). The mean ages in groups A and B were 49.37 ⫾ 13.61 years and 47.80 ⫾ 13.82 years, respectively (P ⫽ .612). The estimated pterygium area over the cornea in group A was 11.38 ⫾ 5.58 mm2 (range, 4.83 to 26.52 mm2; 95% confidence interval, 9.50 to 13.27). This value in group B was 10.44 ⫾ 4.03 mm2 (range, 4.41 to 19.12 mm2; 95% confidence interval, 9.24 to 11.63; P ⫽ .375). One month after surgery, 17 patients (47.2%) in group A and 23 patients (50%) in group B reported foreign body sensation (P ⫽ .803). At this time, 4 cases (11.1%) in group A and 7 cases (15.2%) in group B had red eye (P ⫽ .419). In the following months, there was neither clinically or statistically significant difference in red eye or foreign body sensation between the groups. No case of complication such as dellen formation, persistent corneal epithelial defect, corneal or sclera melting, or infection was noted during 1-year follow-up. In group A, 3 months after the surgical procedure, we found a case with fibrovascular overgrowth over the cornea measuring 0.8 ⫻ 0.9 mm; however, considering our definition for recurrence of at least 1 mm progression of fibrovascular tissue over the cornea, this situation was not clinically
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significant. A case with a small conjunctival cyst near the caruncle was found in group A, which was clinically unremarkable. In group A, 2 patients had whitening of sclera and hypovascularity at the site of excision (Figure 2), which persist at last follow-up (12 months). In a young patient, this was cosmetically unpleasant (a similar whitening developed in the opposite operated eye, too; however, only 1 eye was selected randomly for the analysis). No case of recurrence was noted in group A. In group B, 2 cases (4.3%) of recurrence were noted in the third and sixth months of follow-up. The recurrence rate was not statistically significantly different between study groups (P ⫽ .312, Fisher exact test). In patients with incomplete follow-up, there was no significant complication, except for red eye and foreign body sensation; however, all of them had a follow-up of fewer than 6 weeks and their data would not be conclusive. We checked the data of randomly omitted eyes of bilateral cases, and as mentioned previously, there was only 1 case with the complication of scleral whitening at the site of pterygium excision in these eyes, belonging to group A.
MMC into the neck of pterygium at limbus instead of pterygium head, as originally was recommended by Donnenfeld and associates.20 The rotational flap group in this study consisted of 46 patients with primary pterygium undergoing pterygium surgery with intraoperative application of 0.02% MMC for 2 minutes and rotational conjunctival flap. Except for recurrence, no other complications were found in 12 months of follow-up. Foreign body sensation and red eye were present for a longer period in these patients. Similar to our study, Young and associates used rotational conjunctival flap with adjunctive intraoperative 0.02% MMC and reported a recurrence of 3% after 12 months of follow-up, which is in accordance with our study.21 The small difference in the recurrence rate could be explained based on the differences in definition of recurrence. They defined recurrence as fibrovascular proliferation invading the cornea more than 1.5 mm, whereas our definition was stricter with the limit of 1 mm. In their study, the main postoperative problem was graft injection, which was noted in 41 eyes (61%) at 1 year after surgery. We did not encounter such a high rate of injection in our group B patients. The difference could be because of the longer duration of MMC application by Young and associates (5 minutes vs 2 minutes in our series). In addition, contrary to their technique, we did not suture the conjunctival flap to the limbus and left a 2-mm bare zone adjacent to the limbus that, as mentioned previously,24 could be a reason for a better cosmetic result in our series. They did not mention whether the Vicryl sutures were removed or left to degrade over time; however, we removed the suture to avoid long-term irritation. Racial differences also could be an explanation, because all of their participants were Chinese. Finally, most of the patients subjectively noted as having graft injection in their series had nil injection (60.8%; 45 of 74 eyes), and only 6 eyes (8%) had moderate to severe injection. We had more cases with red eye and foreign body sensation in group B patients, which could be the result of a more surgical manipulation and presence of stitches in the early postoperative phase. In 2006, Ucakhan and Kanpolat studied 43 eyes with pterygium and reported no recurrence or serious complications after 1 year of follow-up for rotational flap technique with a 2-minute intraoperative 0.02% MMC application.25 In another study, Solomon and associates addressed the potential toxic effects of intraoperative MMC on ocular surface and reported long-term results of MMC use on conjunctiva.26 After 6 years, the presence of goblet cells count in the operated eyes was 4 times less than that in the control eyes, which reveals that MMC has a deleterious effect on conjunctiva. In their recent report, Avisar and associates suggested application of MMC before removal of the pterygium head to avoid the potential corneal endothelial cell loss.27 Contrary to the method described by Donnenfeld and associates, to avoid long-standing direct exposure of the
DISCUSSION SEVERAL
RESEARCHERS
INVESTIGATED
THE
OPTIMAL
method for the intraoperative administration of MMC to prevent recurrence of pterygium and to minimize the potential complications. Preoperative subconjunctival injection of MMC avoids direct MMC contact with corneal and conjunctival epithelium, which may be the cause of persistent corneal or conjunctival defect. In addition, MMC is titrated right at the site of the pathologic features, which could reduce unwanted effects.20 In the current study, we had no complications such as dellen formation, persistent corneal epithelial defect, and sclera thinning during 1 year of follow-up with this method. Donnenfeld and associates, pioneers in human studies of subconjunctival injection of MMC for pterygium surgery, reported a recurrence rate of 6% in 36 patients undergoing subconjunctival injection of 0.015% MMC 1 month before bare sclera pterygium excision with a follow-up of 24 months.20 They concluded that subconjunctival injection allows exact titration of MMC delivery to the activated fibroblast and minimizes epithelial toxicity. We had no recurrence (more than 1 mm overgrowth) in group A patients, which may be the result of recruiting only primary pterygium cases in our study and to a higher concentration of MMC used (0.020% vs 0.015%). Avisar and associates reported no recurrence after 18 months of follow-up in 27 patients who underwent simultaneous cataract and pterygium excision with subconjunctival injection of 0.015% MMC 1 month before surgery; there had been just 1 case of recurrence having 2 previous surgical procedures for pterygium.23 Similar to our techniques for subconjunctival MMC injection, they injected 196
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cornea to MMC and the resultant endothelial cell loss, we injected subconjunctival MMC at the limbus and not to the pterygium head.20 This is in accordance with the recommendation of Avisar and associates on timing of MMC application.27 We believe that preoperative subconjunctival injection of MMC into the pterygium neck would be protective for corneal endothelium; however, further investigation for this potential benefit is warranted. In addition, we had no recurrence in our series, which could be the result of our higher dose of MMC or to titrating the MMC at the right site of abnormal fibroblasts. There may be safety concerns about the long-term scleral exposure to MMC in our group A patients. However, the safety of the procedure had been addressed previously in animal research,28 and in human study for the treatment of glaucoma,29 ocular cicatricial pemphigoid,30 and pterygium.20,23 In addition, Chang and associates, in an ultrastructural study of the tissue effect of subconjunctival MMC injection before pterygium surgery in 4 patients, demonstrated that epithelial cells of the treated pterygium remained unchanged.31 However, stromal fibroblasts demonstrated a decreased number, were oval rather than spindle-shaped, and had shrunken cytoplasmic processes. Collagen and elastic fibers showed decreased density and were disorganized and degenerated. Capillary endothelial cells were thickened and swollen, with narrow or obliterated lumens. Axonal swelling and demyelination were observed. These are consistent with the clinical findings on the effectiveness of this surgical method. In addition, as stressed by Donnenfeld and associates, the presence of multiple foci of normal goblet cells in the light microscopy specimen argues strongly for the health of the epithelium overlying the area of treatment.20 This is contrary to the finding of decreased epithelial goblet cells with intraoperative application of MMC.26 The current study demonstrated some advantages and disadvantages of either method used for pterygium excision. Preoperative administration of MMC has the potential advantages of ease of technique, surgical time reduction, lower recurrence rate, and less intraoperative bleeding; however, the possibility of long-term MMC side effects, such as scleral necrosis and cosmetic problems with unpleasant scleral whit-
ening, are the drawbacks of the technique. Scleral whitening could be a signifying sign of scleral necrosis; however, pathologic evaluation is required for accurate characterization of these lesions. Nevertheless, intraoperative MMC in conjunction with a rotational conjunctival flap is cosmetically more acceptable with no conjunctival whitening or hypovascularity, although it has longer surgical time and the presence of sutures induce more foreign body sensation and conjunctival hyperemia. In addition, manipulation of superior conjunctiva and inherent cicatrices formation would be unfavorable, especially in the case of future needs for glaucoma filtration surgery. Because the superior conjunctiva, shielded from solar damage, is the preferred location for obtaining a conjunctival flap in pterygium surgery, a limited alternative would be available for harvesting the required conjunctiva in this surgical technique. Our study has several limitations. We had a limited sample size that could reduce the power of our study. However, its sample size is comparable with that of most similar studies, and to the best of our knowledge, this is the only study comparing these 2 surgical methods. Our follow-up period is acceptable for detection of most shortand medium-term potential complications of the surgery; however, long-term complications could not be ruled out based on our study. Notably, there are reports on complications such as scleral melting and necrosis up to 16 years after surgery.32 Obviously, designing such a long-lasting longitudinal study to detect this rare, late complication would be difficult, if not impractical. In addition, such a complication could occur in bare scleral pterygium excision even without adjunctive antimetabolite, and inference about a causal relationship would not be precise.33 We can conclude that subconjunctival injection of MMC 1 month before the bare scleral excision of pterygium is a simple and quick surgical procedure and is at least as effective as a conjunctival rotational flap with intraoperative MMC application in terms of recurrence and complication rate for primary pterygium treatment. However, studies with a larger sample size, longer follow-up period, and more diverse patient population should be designed for evaluation of long-term success and potential complications in a more comprehensive clinical situation.
SUPPORTED BY A RESEARCH GRANT FROM MASHHAD UNIVERSITY OF MEDICAL SCIENCES, MASHHAD, IRAN. THE AUTHORS indicate no financial conflict of interest. Involved in design and conduct of the study (H.K., M.E.R., R.D., M.F.G.); Collection of data (M.F.G.); Management of data (R.D., M.T.S., H.G.); Analysis and interpretation of data (R.D.); Preparation of the manuscript (R.D., H.G.); and Review and approval of the manuscript (R.D.). All of the participants provided written informed consent and the research adhered to the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of Mashhad University of Medical Sciences. The authors thank Ghasem Fakhraie for editorial assistance and critical comments on the text.
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3. Todani A, Melki SA. Pterygium: current concepts in pathogenesis and treatment. Int Ophthalmol Clin 2009;49(1):21–30. 4. Solomon AS. Pterygium. Br J Ophthalmol 2006;90(6):665– 666. 5. Kria L, Ohira A, Amemiya T. Immunohistochemical localization of basic fibroblast growth factor, platelet derived
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20. Donnenfeld ED, Perry HD, Fromer S, Doshi S, Solomon R, Biser S. Subconjunctival mitomycin C as adjunctive therapy before pterygium excision. Ophthalmology 2003;110(5):1012–1016. 21. Young AL, Tam PM, Leung GY, Cheng LL, Lam PT, Lam DS. Prospective study on the safety and efficacy of combined conjunctival rotational autograft with intraoperative 0.02% mitomycin C in primary pterygium excision. Cornea 2009; 28(2):166 –169. 22. Kleis W, Pico G. Thio-TEPA therapy to prevent postoperative pterygium occurrence and neovascularization. Am J Ophthalmol 1973;76(3):371–373. 23. Avisar R, Bar S, Weinberger D. Preoperative injection of mitomycin C in combined pterygium and cataract surgery. Cornea 2005;24(4):406 – 409. 24. Avisar R, Weinberger D. Pterygium surgery with mitomycin C: how much sclera should be left bare? Cornea 2003;22(8): 721–725. 25. Ucakhan OO, Kanpolat A. Combined “symmetrical conjunctival flap transposition” and intraoperative low-dose mitomycin C in the treatment of primary pterygium. Clin Experiment Ophthalmol 2006;34(3):219 –225. 26. Solomon A, Kaiserman I, Raiskup FD, Landau D, FruchtPery J. Long-term effects of mitomycin C in pterygium surgery on scleral thickness and the conjunctival epithelium. Ophthalmology 2004;111(8):1522–1527. 27. Avisar R, Apel I, Avisar I, Weinberger D. Endothelial cell loss during pterygium surgery: importance of timing of mitomycin C application. Cornea 2009;28(8):879 – 881. 28. Kee C, Pelzek CD, Kaufman PL. Mitomycin C suppresses aqueous humor flow in cynomolgus monkeys. Arch Ophthalmol 1995;113(2):239 –242. 29. Gandolfi SA, Vecchi M, Braccio L. Decrease of intraocular pressure after subconjunctival injection of mitomycin in human glaucoma. Arch Ophthalmol 1995;113(5):582–585. 30. Donnenfeld ED, Perry HD, Wallerstein A, et al. Subconjunctival mitomycin C for the treatment of ocular cicatricial pemphigoid. Ophthalmology 1999;106(1):72–78. 31. Chang YS, Chen WC, Tseng SH, Sze CI, Wu CL. Subconjunctival mitomycin C before pterygium excision: an ultrastructural study. Cornea 2008;27(4):471– 475. 32. Wan Norliza WM, Raihan IS, Azwa JA, Ibrahim M. Scleral melting 16 years after pterygium excision with topical mitomycin C adjuvant therapy. Cont Lens Anterior Eye 2006; 29(4):165–167. 33. Gokhale NS, Samant R. Surgically induced necrotizing scleritis after pterygium surgery. Indian J Ophthalmol 2007; 55(2):144 –146.
growth factor, transforming growth factor-beta and tumor necrosis factor-alpha in the pterygium. Acta Histochem 1996;98(2):195–201. Jin J, Guan M, Sima J, et al. Decreased pigment epitheliumderived factor and increased vascular endothelial growth factor levels in pterygia. Cornea 2003;22(5):473– 477. Di GN, Wakefield D, Coroneo MT. UVB-mediated induction of cytokines and growth factors in pterygium epithelial cells involves cell surface receptors and intracellular signaling. Invest Ophthalmol Vis Sci 2006;47(6):2430 –2437. Chiang CC, Cheng YW, Lin CL, et al. Cyclooxygenase 2 expression in pterygium. Mol Vis 2007;13:635– 638. Adiguzel U, Karabacak T, Sari A, Oz O, Cinel L. Cyclooxygenase-2 expression in primary and recurrent pterygium. Eur J Ophthalmol 2007;17(6):879 – 884. Di GN, Coroneo MT, Wakefield D. UVB-elicited induction of MMP-1 expression in human ocular surface epithelial cells is mediated through the ERK1/2 MAPK-dependent pathway. Invest Ophthalmol Vis Sci 2003;44(11):4705– 4714. Di GN, Coroneo M, Wakefield D. Epidermal growth factor receptor signaling is partially responsible for the increased matrix metalloproteinase-1 expression in ocular epithelial cells after UVB radiation. Am J Pathol 2005;167(2):489 – 503. Hosseini H, Nejabat M, Khalili MR. Bevacizumab (Avastin) as a potential novel adjunct in the management of pterygia. Med Hypotheses 2007;69(4):925–927. Fossarello M, Peiretti E, Zucca I, Perra MT, Serra A. Photodynamic therapy of pterygium with verteporfin: a preliminary report. Cornea 2004;23(4):330 –338. Hirst LW. The treatment of pterygium. Surv Ophthalmol 2003;48(2):145–180. Frucht-Pery J, Siganos CS, Ilsar M. Intraoperative application of topical mitomycin C for pterygium surgery. Ophthalmology 1996;103(4):674 – 677. Singh G, Wilson MR, Foster CS. Mitomycin eye drops as treatment for pterygium. Ophthalmology 1988;95(6):813– 821. Helal M, Messiha N, Amayem A, el-Maghraby A, Elsherif Z, Dabees M. Intraoperative mitomycin-C versus postoperative topical mitomycin-C drops for the treatment of pterygium. Ophthalmic Surg Lasers 1996;27(8):674 – 678. Caliskan S, Orhan M, Irkec M. Intraoperative and postoperative use of mitomycin-C in the treatment of primary pterygium. Ophthalmic Surg Lasers 1996;27(7):600 – 604. Rubinfeld RS, Stein RM. Topical mitomycin-C for pterygia: is single application appropriate? Ophthalmic Surg Lasers 1997;28(8):662– 669.
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To evaluate and compare the recurrence rates and complications between 2 therapeutic methods for primary pterygium: subconjunctival injection of mitomycin C (MMC) 1 month before bare scleral excision and conjunctival rotational flap with intraoperative MMC use. ● DESIGN: Prospective, interventional, randomized clinical trial. ● METHODS: SETTING: Institutional clinical trial in a tertiary, specialty eye hospital. STUDY POPULATION AND INTERVENTION: We included 82 eyes diagnosed with primary pterygium and randomly allocated them into 2 groups. Group A consisted of 36 eyes treated with subconjunctival injection of 0.02% MMC 1 month before bare scleral excision, and group B comprised 46 eyes that underwent conjunctival rotational flap with intraoperative 0.02% MMC for 2 minutes. Follow-up periods were at least 12 months (range, 12 to 18 months). MAIN OUTCOME MEASURE: Recurrence and complication rate in each arm of study. ● RESULTS: During the 1-year follow-up, 2 cases of clinical recurrence in third and sixth month of follow-up occurred in group B (recurrence rate, 4.3%). In group A, there was no clinically significant recurrence, but 2 cases of hypovascularity and whitening of sclera at the site of pterygium excision was observed. There was no other serious complication. There was no statistically significant difference between groups for recurrence rate, mean age, sex, or pterygium area. ● CONCLUSIONS: Subconjunctival injection of MMC 0.02% (0.1 ml of 0.02% solution) 1 month before bare scleral excision is a quick, easy, and safe surgical procedure and is at least as effective as conjunctival rotational flap with intraoperative MMC for 2 minutes. (Am J Ophthalmol 2010;150:193–198. © 2010 by Elsevier Inc. All rights reserved.)
Accepted for publication Mar 24, 2010. From the Khatam Anbia Eye Hospital, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (H.K., M.E.R., R.D., M.F.G., H.G.); and the Department of Biostatistics and Social Sciences, Ghaem General Hospital, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (M.T.S.). Inquiries to Ramin Daneshvar, Khatam Anbia Eye Hospital, Ghareni Boulevard, Mashhad 91959-61151, Iran; e-mail: [email protected] 0002-9394/$36.00 doi:10.1016/j.ajo.2010.03.006
©
2010 BY
P
TERYGIUM IS A FIBROVASCULAR OVERGROWTH OF
conjunctival tissue encroaching on the cornea from limbus toward the center that resembles an insect wing.1 Overall prevalence of the disease is 5% to 15% and increases in tropical areas, which may suggest the pivotal role of ultraviolet (UV) light as the cause of the disease.2 UV exposure is widely accepted to be the single most important etiologic factor in pterygium pathogenesis.3 UV light may produce damage to the cellular DNA, RNA, and extracellular matrix4 and may induce expression of cytokines and growth factors important in the development of pterygium.5–7 However, the exact pathogenesis of pterygium remains uncertain. Other mechanisms have been proposed, including the role of cellular immunity through pathways involving cyclooxygenase-28,9 and matrix metalloproteinases.10,11 Another proposed mechanism focuses on the role of vascular proliferation in the development of pterygium.12,13 Generally, pterygium can be considered a proliferative, invasive lesion with focal limbal breakdown associated with excessive UV exposure. There are several indications for pterygium excision, such as decreased visual acuity resulting from visual axis involvement, tear film break-up, and/or irregular eye movement limitation; eye irritation and discomfort; inability to wear contact lenses; difficulty in performing refractive surgery; uncertainty about the diagnosis; and cosmetic concerns.14 Many different surgical techniques have been tried for pterygium removal with variable success rates. The most convenient technique is simple excision of pterygium. However, bare sclera technique of pterygium excision without adjuvant therapies (chemotherapy and radiation) has recurrence rates of 29.7% to 88.9%.15,16 In different studies, the adjuvant therapy with different concentrations (0.01% to 0.4%) of mitomycin C (MMC) has been associated with a 2.7% to 42.9% decrease in recurrence rate.17–19 Concerns about the sight-threatening side effects of adjuvant therapy have made alternative therapeutic measures as a popular research topic. In an attempt to decrease ocular surface exposure to intraoperative antimetabolites, subconjunctival injection of MMC has been proposed with a recurrence rate of 6%.20 Recently, combination of intraoperative MMC and rotational conjunctival flap has been reported as a highly efficacious treatment for
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FIGURE 1. Photograph showing estimation of pterygium surface on cornea. (Left) Pterygium height, h, and base, b, over the cornea are measured, and the surface area, a, is approximated as a ⴝ bh/2. In this patient, approximate area is 7.56 ⴛ 5.90/2 ⴝ 22.30 mm2. (Right) Actual surface area as calculated by software (22.78 mm2).
pterygium, with a reported recurrence rate of 3%.21 However, differences in patient inclusion criteria and the noncomparative nature of these studies have made conclusive decisions about the choice procedure difficult, if not impossible. The purpose of this study was to compare the 2 recently introduced surgical approaches (i.e., preoperative subpterygeal MMC injection with later bare sclera excision and intraoperative MMC application with conjunctival rotational flap) in terms of complications and recurrence rates.
checked the precision of the method with the Measuring Tool of Adobe Acrobat software (version 9 Pro Extended; Adobe System Incorporated, Burlington, New Jersey, USA). As evident in Figure 1, the surface area calculated with the equation is in close approximation to the actual surface area calculated by the software. All of the operations were performed by 2 of the authors (H.K. and M.E.R.), both skillful in pterygium surgery with a surgical experience of more than 15 years. In group A, the surgery was performed in 2 stages: in the first, officebased stage, the conjunctiva was anesthetized with instillation of tetracaine eye drops followed by local injection of lidocaine 2%. After waiting for 5 minutes to achieve sufficient anesthesia, and under the slit-lamp viewing, 0.1 mL 0.02% MMC solution (Mitomycin-C Kyowa; Kyowa Hakko Kogyo Co, Ltd, Tokyo, Japan) was injected sublesionally via a 30-gauge insulin syringe and along the limbus at the site of pterygium overgrowth over the cornea. A cotton-tip applicator then was used to compress the needle entry site to prevent MMC egress on the ocular surface. In the end, and in a recombinant position, the eye was irrigated copiously with at least 30 mL balanced salt solution. After injection, all patients received 0.5% chloramphenicol (Sina Darou, Tehran, Iran) and 0.1% betamethasone (Sina Darou) eye drops every 6 hours for 1 week. Follow-up visits were scheduled for 1 day, 1 week, and 1 month later. In the second stage, 1 month after the initial injection, bare scleral excision of pterygium was performed, as has been described previously.20 The eye was pressure patched and topical medications were restarted at the first postoperative day. At the second postoperative visit 1 week later, chloramphenicol eye drop was discontinued and betamethasone was substituted with topical 0.1% fluorometholone (Fluocort; Sina Darou) every 6 hours for 1 month. In group B, with a modified Pico technique,22 the patients underwent pterygium excision after local anesthe-
METHODS THIS WAS A RANDOMIZED CLINICAL TRIAL CONDUCTED ON
all eligible patients referred with a diagnosis of primary pterygium to a tertiary referral eye hospital in northeastern Iran (Khatam Anbia Eye Hospital) from October 2007 through June 2009. Pregnant or breast-feeding women and patients with a history of previous ocular surgeries; ocular diseases such as glaucoma, herpetic keratitis, and trachoma; or any autoimmune disease were excluded. Patients were allocated randomly into 2 groups. Randomization was carried out using envelopes containing random digits. Group A patients (envelopes with odd digits) underwent subconjunctival injection of 0.02% MMC 1 month before bare scleral excision. Group B patients (envelopes with even digits) underwent conjunctival excision with a rotational flap from the superior conjunctiva and intraoperative 0.02% MMC. A comprehensive ophthalmic examination, including best-corrected visual acuity testing, slit-lamp examination, Goldmann applanation tonometry, and fundus examination, was carried out for all participants. Assuming a pterygium to have a triangular shape, corneal surface area covered by pterygium, a, was estimated by multiplying maximum width, b, at pterygium base to half of its length, h: a ⫽ bh/2. We found this approximation to be a user-friendly approach with acceptable accuracy. We 194
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sia with topical tetracaine and local subconjunctival injection of lidocaine 2%. Pterygium was grasped at the limbus and avulsed from corneal surface with a muscle hook. A Wescott scissors was used to remove the pterygium body, and the corneal and sclera surfaces were polished with a no. 15 Bard-Parker blade. Minimal cautery was performed to control bleeding, and 0.02% MMC solution was applied to the bared scleral bed for 2 minutes, followed by copious irrigation of the ocular surface with at least 30 mL balanced salt solution. After releasing the superior conjunctiva, a conjunctival flap was rotated and fixed over the bare sclera using 8-0 Vicryl (Surgicryl; SMI AG, Hünningen, Belgium) stitches to cover the resection site, except a 2-mm zone adjacent to the limbus. Finally, topical ointments of erythromycin and hydrocortisone were applied and the eye was pressure patched. On the first postoperative day, 0.5% chloramphenicol and 0.1% betamethasone eye drops were administered every 6 hours for 1 week. The patients were visited 1 week later, and fluorometholone eye drops were administered (every 6 hours for 1 month) instead of betamethasone. If not degraded, the Vicryl sutures were removed at the third postoperative week. In both groups, follow-up visits were scheduled 1, 3, 6, 9, and 12 months after surgery, and a complete set of ophthalmic examinations was repeated with special focus on probable complications such as dellen formation, persistent corneal epithelial defect, recurrence, and scleral necrosis. After surgery, an overgrowth of fibrovascular tissue over the corneal surface of more than 1.0 mm was considered a recurrence, as has been described previously.20 One of the authors (M.F.G.), blinded about the study groups, performed all ophthalmic examinations; however, because of apparent differences between the ocular surface appearance of the study groups, especially in the early phase, there was practical limitation to the blinding procedure at the postoperative first month visit. In patients with bilateral pterygium requiring surgical intervention, a similar procedure was performed on both eyes; however, only 1 eye per subject was included randomly in the final analysis. Patients without regular follow-up were omitted from the study. Because some of participants were Afghani refugees, recruitment for follow-up examination was impossible after the first postoperative visits. We could assume that they had no major complication or recurrence; however, to be precise, we did not include them in the final analysis. The complication rate was compared between the 2 groups using chi-square and Fisher exact tests. Intergroup changes for continuous parametric variables were evaluated by the unpaired Student t test. All statistical analyses was performed with SPSS version 15 (SPSS Science Inc, Chicago, Illinois, USA). For all measurements, a 2-tailed test was used, and the statistical significance level was set at P ⬍ .05. VOL. 150, NO. 2
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FIGURE 2. Photograph showing whitening of sclera after pterygium surgery with preoperative subconjunctival injection of mitomycin C and subsequent bare sclera technique.
RESULTS EIGHTY-TWO EYES OF 82 PATIENTS WERE ENROLLED IN THE
study, including 36 eyes in group A and 46 eyes in group B. Initially, group A comprised of 66 eyes; however, 18 eyes were excluded because of incomplete follow-up and 12 eyes were omitted randomly in bilateral cases, leaving 36 eyes of 36 patients for the final analysis. Group B included 51 patients; however, 7 eyes of 5 patients with incomplete follow-up visits and 4 randomly selected eyes in bilateral cases were excluded from the final analysis. Finally, 46 eyes of 46 patients were evaluated in group B. There were 18 (50%) and 24 (52.2%) females in groups A and B, respectively (P ⫽ .840). The mean age of all patients was 48.48 ⫾ 13.67 years (range, 20 to 80 years). The mean ages in groups A and B were 49.37 ⫾ 13.61 years and 47.80 ⫾ 13.82 years, respectively (P ⫽ .612). The estimated pterygium area over the cornea in group A was 11.38 ⫾ 5.58 mm2 (range, 4.83 to 26.52 mm2; 95% confidence interval, 9.50 to 13.27). This value in group B was 10.44 ⫾ 4.03 mm2 (range, 4.41 to 19.12 mm2; 95% confidence interval, 9.24 to 11.63; P ⫽ .375). One month after surgery, 17 patients (47.2%) in group A and 23 patients (50%) in group B reported foreign body sensation (P ⫽ .803). At this time, 4 cases (11.1%) in group A and 7 cases (15.2%) in group B had red eye (P ⫽ .419). In the following months, there was neither clinically or statistically significant difference in red eye or foreign body sensation between the groups. No case of complication such as dellen formation, persistent corneal epithelial defect, corneal or sclera melting, or infection was noted during 1-year follow-up. In group A, 3 months after the surgical procedure, we found a case with fibrovascular overgrowth over the cornea measuring 0.8 ⫻ 0.9 mm; however, considering our definition for recurrence of at least 1 mm progression of fibrovascular tissue over the cornea, this situation was not clinically
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significant. A case with a small conjunctival cyst near the caruncle was found in group A, which was clinically unremarkable. In group A, 2 patients had whitening of sclera and hypovascularity at the site of excision (Figure 2), which persist at last follow-up (12 months). In a young patient, this was cosmetically unpleasant (a similar whitening developed in the opposite operated eye, too; however, only 1 eye was selected randomly for the analysis). No case of recurrence was noted in group A. In group B, 2 cases (4.3%) of recurrence were noted in the third and sixth months of follow-up. The recurrence rate was not statistically significantly different between study groups (P ⫽ .312, Fisher exact test). In patients with incomplete follow-up, there was no significant complication, except for red eye and foreign body sensation; however, all of them had a follow-up of fewer than 6 weeks and their data would not be conclusive. We checked the data of randomly omitted eyes of bilateral cases, and as mentioned previously, there was only 1 case with the complication of scleral whitening at the site of pterygium excision in these eyes, belonging to group A.
MMC into the neck of pterygium at limbus instead of pterygium head, as originally was recommended by Donnenfeld and associates.20 The rotational flap group in this study consisted of 46 patients with primary pterygium undergoing pterygium surgery with intraoperative application of 0.02% MMC for 2 minutes and rotational conjunctival flap. Except for recurrence, no other complications were found in 12 months of follow-up. Foreign body sensation and red eye were present for a longer period in these patients. Similar to our study, Young and associates used rotational conjunctival flap with adjunctive intraoperative 0.02% MMC and reported a recurrence of 3% after 12 months of follow-up, which is in accordance with our study.21 The small difference in the recurrence rate could be explained based on the differences in definition of recurrence. They defined recurrence as fibrovascular proliferation invading the cornea more than 1.5 mm, whereas our definition was stricter with the limit of 1 mm. In their study, the main postoperative problem was graft injection, which was noted in 41 eyes (61%) at 1 year after surgery. We did not encounter such a high rate of injection in our group B patients. The difference could be because of the longer duration of MMC application by Young and associates (5 minutes vs 2 minutes in our series). In addition, contrary to their technique, we did not suture the conjunctival flap to the limbus and left a 2-mm bare zone adjacent to the limbus that, as mentioned previously,24 could be a reason for a better cosmetic result in our series. They did not mention whether the Vicryl sutures were removed or left to degrade over time; however, we removed the suture to avoid long-term irritation. Racial differences also could be an explanation, because all of their participants were Chinese. Finally, most of the patients subjectively noted as having graft injection in their series had nil injection (60.8%; 45 of 74 eyes), and only 6 eyes (8%) had moderate to severe injection. We had more cases with red eye and foreign body sensation in group B patients, which could be the result of a more surgical manipulation and presence of stitches in the early postoperative phase. In 2006, Ucakhan and Kanpolat studied 43 eyes with pterygium and reported no recurrence or serious complications after 1 year of follow-up for rotational flap technique with a 2-minute intraoperative 0.02% MMC application.25 In another study, Solomon and associates addressed the potential toxic effects of intraoperative MMC on ocular surface and reported long-term results of MMC use on conjunctiva.26 After 6 years, the presence of goblet cells count in the operated eyes was 4 times less than that in the control eyes, which reveals that MMC has a deleterious effect on conjunctiva. In their recent report, Avisar and associates suggested application of MMC before removal of the pterygium head to avoid the potential corneal endothelial cell loss.27 Contrary to the method described by Donnenfeld and associates, to avoid long-standing direct exposure of the
DISCUSSION SEVERAL
RESEARCHERS
INVESTIGATED
THE
OPTIMAL
method for the intraoperative administration of MMC to prevent recurrence of pterygium and to minimize the potential complications. Preoperative subconjunctival injection of MMC avoids direct MMC contact with corneal and conjunctival epithelium, which may be the cause of persistent corneal or conjunctival defect. In addition, MMC is titrated right at the site of the pathologic features, which could reduce unwanted effects.20 In the current study, we had no complications such as dellen formation, persistent corneal epithelial defect, and sclera thinning during 1 year of follow-up with this method. Donnenfeld and associates, pioneers in human studies of subconjunctival injection of MMC for pterygium surgery, reported a recurrence rate of 6% in 36 patients undergoing subconjunctival injection of 0.015% MMC 1 month before bare sclera pterygium excision with a follow-up of 24 months.20 They concluded that subconjunctival injection allows exact titration of MMC delivery to the activated fibroblast and minimizes epithelial toxicity. We had no recurrence (more than 1 mm overgrowth) in group A patients, which may be the result of recruiting only primary pterygium cases in our study and to a higher concentration of MMC used (0.020% vs 0.015%). Avisar and associates reported no recurrence after 18 months of follow-up in 27 patients who underwent simultaneous cataract and pterygium excision with subconjunctival injection of 0.015% MMC 1 month before surgery; there had been just 1 case of recurrence having 2 previous surgical procedures for pterygium.23 Similar to our techniques for subconjunctival MMC injection, they injected 196
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cornea to MMC and the resultant endothelial cell loss, we injected subconjunctival MMC at the limbus and not to the pterygium head.20 This is in accordance with the recommendation of Avisar and associates on timing of MMC application.27 We believe that preoperative subconjunctival injection of MMC into the pterygium neck would be protective for corneal endothelium; however, further investigation for this potential benefit is warranted. In addition, we had no recurrence in our series, which could be the result of our higher dose of MMC or to titrating the MMC at the right site of abnormal fibroblasts. There may be safety concerns about the long-term scleral exposure to MMC in our group A patients. However, the safety of the procedure had been addressed previously in animal research,28 and in human study for the treatment of glaucoma,29 ocular cicatricial pemphigoid,30 and pterygium.20,23 In addition, Chang and associates, in an ultrastructural study of the tissue effect of subconjunctival MMC injection before pterygium surgery in 4 patients, demonstrated that epithelial cells of the treated pterygium remained unchanged.31 However, stromal fibroblasts demonstrated a decreased number, were oval rather than spindle-shaped, and had shrunken cytoplasmic processes. Collagen and elastic fibers showed decreased density and were disorganized and degenerated. Capillary endothelial cells were thickened and swollen, with narrow or obliterated lumens. Axonal swelling and demyelination were observed. These are consistent with the clinical findings on the effectiveness of this surgical method. In addition, as stressed by Donnenfeld and associates, the presence of multiple foci of normal goblet cells in the light microscopy specimen argues strongly for the health of the epithelium overlying the area of treatment.20 This is contrary to the finding of decreased epithelial goblet cells with intraoperative application of MMC.26 The current study demonstrated some advantages and disadvantages of either method used for pterygium excision. Preoperative administration of MMC has the potential advantages of ease of technique, surgical time reduction, lower recurrence rate, and less intraoperative bleeding; however, the possibility of long-term MMC side effects, such as scleral necrosis and cosmetic problems with unpleasant scleral whit-
ening, are the drawbacks of the technique. Scleral whitening could be a signifying sign of scleral necrosis; however, pathologic evaluation is required for accurate characterization of these lesions. Nevertheless, intraoperative MMC in conjunction with a rotational conjunctival flap is cosmetically more acceptable with no conjunctival whitening or hypovascularity, although it has longer surgical time and the presence of sutures induce more foreign body sensation and conjunctival hyperemia. In addition, manipulation of superior conjunctiva and inherent cicatrices formation would be unfavorable, especially in the case of future needs for glaucoma filtration surgery. Because the superior conjunctiva, shielded from solar damage, is the preferred location for obtaining a conjunctival flap in pterygium surgery, a limited alternative would be available for harvesting the required conjunctiva in this surgical technique. Our study has several limitations. We had a limited sample size that could reduce the power of our study. However, its sample size is comparable with that of most similar studies, and to the best of our knowledge, this is the only study comparing these 2 surgical methods. Our follow-up period is acceptable for detection of most shortand medium-term potential complications of the surgery; however, long-term complications could not be ruled out based on our study. Notably, there are reports on complications such as scleral melting and necrosis up to 16 years after surgery.32 Obviously, designing such a long-lasting longitudinal study to detect this rare, late complication would be difficult, if not impractical. In addition, such a complication could occur in bare scleral pterygium excision even without adjunctive antimetabolite, and inference about a causal relationship would not be precise.33 We can conclude that subconjunctival injection of MMC 1 month before the bare scleral excision of pterygium is a simple and quick surgical procedure and is at least as effective as a conjunctival rotational flap with intraoperative MMC application in terms of recurrence and complication rate for primary pterygium treatment. However, studies with a larger sample size, longer follow-up period, and more diverse patient population should be designed for evaluation of long-term success and potential complications in a more comprehensive clinical situation.
SUPPORTED BY A RESEARCH GRANT FROM MASHHAD UNIVERSITY OF MEDICAL SCIENCES, MASHHAD, IRAN. THE AUTHORS indicate no financial conflict of interest. Involved in design and conduct of the study (H.K., M.E.R., R.D., M.F.G.); Collection of data (M.F.G.); Management of data (R.D., M.T.S., H.G.); Analysis and interpretation of data (R.D.); Preparation of the manuscript (R.D., H.G.); and Review and approval of the manuscript (R.D.). All of the participants provided written informed consent and the research adhered to the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of Mashhad University of Medical Sciences. The authors thank Ghasem Fakhraie for editorial assistance and critical comments on the text.
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