Risk Factors for Ocular Surface Squamous Neoplasia Recurrence after Treatment With Topical Mitomycin C and Interferon Alpha-2b JENNA BESLEY, JUANITA PAPPALARDO, GRAHAM A. LEE, LAWRENCE W. HIRST, AND STEPHEN J. VINCENT PURPOSE:
To determine the rate of recurrence and associated risk factors after the use of mitomycin C (MMC), interferon alpha-2b, or both for management of noninvasive ocular surface squamous neoplasia (OSSN). DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Clinical practice setting of 135 patients treated consecutively with topical MMC (0.4 mg/mL), interferon alpha-2b (1 million units/mL), or both for OSSN observed for clinical recurrence. RESULTS: Clinical recurrences were diagnosed in 19 (14.1%) of 135 eyes after topical treatment. The mean time to recurrence was 17.2 months (range, 4 to 61 months), with 14 eyes (73.7%) recurring within a 2-year period. There was no greater risk of recurrence identified for variables including lesion size, lesion location, gender, age, treatment type, or treatment duration. Post hoc log-rank pairwise comparisons revealed that lesions initially treated using surgery alone had significantly reduced time to recurrence (21.1 ± 5.6 months) compared with previous topical treatment with MMC (with or without surgery; 29.6 ± 4.7 months; P [ .04) and primary OSSN (23.2 ± 1.8 months; P [ .09). CONCLUSIONS: Topical MMC and interferon alpha-2b are an effective treatment method for a wide range of noninvasive OSSNs. Topical therapy avoids the morbidity of excisional surgery with equivalent or reduced recurrence rates and should be considered as primary therapy. (Am J Ophthalmol 2014;157:287–293. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Oct 21, 2013. From the Department of Ophthalmology, City Eye Centre, Brisbane, Australia (J.B., J.P., G.A.L.); the Department of Ophthalmology, University of Queensland, Brisbane, Australia (J.P., G.A.L., L.W.H.); the Department of Ophthalmology, Royal Brisbane Hospital, Brisbane, Australia (G.A.L.); the Department of Ophthalmology, The Australian Pterygium Centre, Brisbane, Australia (L.W.H.); the Department of Ophthalmology, Queensland Eye Institute, Brisbane, Australia (L.W.H.); and the School of Optometry and Vision Science, Queensland University of Technology, Kelvin Grove, Australia (S.J.V.). Inquiries to Graham A. Lee, City Eye Centre, 10/135 Wickham Terrace, Brisbane, Queensland 4000, Australia; e-mail: eye@cityeye. com.au 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.012
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2014 BY
O
CULAR SURFACE SQUAMOUS NEOPLASIA (OSSN)
encompasses a spectrum of lesions arising from the squamous cells of the conjunctiva, cornea, or both.1 Excessive exposure to ultraviolet B radiation is the major etiologic factor; however, other causes, such as human papillomavirus types 16 and 18 and HIV seropositivity, also have been implicated.1,2 OSSN is described as a relatively low-grade malignancy because invasive disease is uncommon and tends to be preceded by dysplasia and carcinoma in situ.1 However, a lack of appropriate and effective treatment for OSSN can result in malignant change followed by local invasion and, rarely, metastasis. Surgical excision with adequate margins and adjunctive cryotherapy is a well-established treatment for OSSN, although this is an invasive option with numerous disadvantages. Tabin and associates described high recurrence rates after surgical excision (33% at 10 years despite histologically clear surgical margins).3 Evidence suggests that the microscopic changes associated with OSSN extend beyond the macroscopic margin; thus, surgical excision to achieve clear margins is difficult.4 Techniques to examine tumor margins and conserve normal tissue such as Moh micrographic surgery have been adapted for oculoplastic tumor work; however, frozen sections are challenging to perform on small fragile corneal or conjunctival specimens.5 Additionally, because of the multifocal nature of OSSN, surgical excision results in wide collateral damage to adjacent areas of normal epithelium, including the potential for limbal stem cell deficiency and visually disturbing corneal scarring.4 A recent study by Galor and associates examined the rates of recurrence after surgical excision using various techniques and found them to be 10% at 1 year and 21% at 5 years.6 The authors identified tarsal involvement and positive pathologic margins as the strongest predictors of clinical recurrence after surgical excision of OSSN lesions. High-grade lesions, large lesions, and a previous patient history of OSSN were associated with an increased risk of tumor recurrence. The mean time to clinical recurrence after surgical excision was 2.5 years. The purpose of this study was to identify predictive factors of OSSN recurrence after topical treatment of noninvasive OSSN using a large, retrospective case series. The study examined the rates of recurrence of OSSN after the use of topical treatment for both primary therapy and for
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RIGHTS RESERVED.
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the treatment of recurrences using mitomycin C (MMC), interferon alpha-2b (IFN), or both. Identification of risks for recurrence potentially may allow for tailored management plans, with the aim of improving treatment success.
METHODS IN THIS RETROSPECTIVE, NONCOMPARATIVE, INTERVEN-
tional case series study, clinical data of 143 eyes of 135 patients diagnosed with OSSN were reviewed. Approval to conduct this study was obtained prospectively from the Royal Australian and New Zealand College of Ophthalmologists Human Research Ethics Committee (study no. 29.11). The National Health and Medical Research Council guidelines were followed, and it adhered to the tenets of the Declaration of Helsinki. Database information allowed identification of all prescriptions for MMC or IFN dispensed consecutively by 2 oncology pharmacies: the Royal Brisbane and Women’s Hospital, a tertiary referral hospital in Brisbane, Queensland, Australia, and Custom Care Compounding Pharmacy in Dural, New South Wales, Australia. Eligible patients were those whose first prescription was dispensed between December 2001 and December 2012. Of these patients, those who were treated by a single ophthalmologist (G.A.L.) were chosen as candidates for inclusion in the study. This was to ensure uniformity in treatment regimen and clinical examination techniques. OSSN was diagnosed principally by clinical examination, but in some equivocal cases, by histology. All cases were primary or recurrent noninvasive lesions. Invasive lesions were excluded on the basis of tethering to the underlying sclera on indirect palpation of the lesion through the lid. For those patients with recurrent disease, previous treatment methods were recorded. Treatment with MMC or IFN continued until either clinical resolution was achieved or the treatment was deemed to have failed. Treatment failure was defined as lack of response after 3 to 4 cycles of treatment with MMC, failure to achieve complete clinical resolution after up to 6 months of treatment with IFN, or both. Patients with fewer than 6 months of follow-up after clinical resolution were excluded from this study. All patients underwent a comprehensive ophthalmic examination at the commencement of treatment and at all follow-up visits, including uncorrected and corrected visual acuity, intraocular pressure measurement, and slitlamp examination with photography. The diagnosis of OSSN was made by a single ophthalmologist experienced in examining ocular tumors (G.A.L.). In the primary cases, this was performed clinically, relying on the characteristic features of OSSN: gelatinous, papilliform, or leukoplakic lesion with characteristic tufted, superficial, so-called corkscrew vessels. This avoided more invasive incisional 288
biopsy; however, in cases where the clinical diagnosis was uncertain, a scraping or biopsy sample was obtained for histologic diagnosis. Impression cytologic analysis was not available during the course of the study. The location and dimensions of the lesion were recorded at the commencement of treatment, with appropriate measurements obtained using the slit lamp. For purposes of data analysis, the lesions were grouped according to the maximal basal diameter (in millimeters). The MMC and IFN eye drops used in this study were prepared extemporaneously by the oncology pharmacy of the Royal Brisbane and Women’s Hospital, Brisbane, Australia (2001 through 2009) and the Custom Care Compounding Pharmacy, Sydney, Australia (2010 through 2012) under cytotoxic laminar flow conditions. The MMC (Kyowa Kirin, Berkshire, United Kingdom) was prepared at a concentration of 0.04% by reconstituting 2 mg powder with 5 mL of 0.9% saline, filtered and stored in a sterile plastic bottle. The IFN was prepared at a concentration of 1 million IU/mL by diluting 0.67 mL of 18M IU/1.2 mL injectable recombinant IFN (Intron A; Merck & Co., Inc., Whitehouse Station, New Jersey, USA) with 0.9% saline up to 10 mL, filtered and stored in 3 sterile plastic bottles. All side effects reported by the patients or observed during clinical examination were documented. Patients were administered a regimen of MMC 0.04% 4 times daily for 1 week, followed by 3 weeks off treatment. This treatment cycle was repeated until an end point was reached. If necessary, patients were prescribed lubricant eye drops and dexamethasone 1% 4 times daily to resolve minor redness or irritation. Patients were administered IFN 1 million IU/mL 4 times daily if previous treatment with MMC had failed or if they were unable to tolerate MMC as a result of side effects. Again, this treatment was continued until an end point was reached. Patients who failed to respond to topical treatment underwent surgical excision. At each follow-up visit, ophthalmic examination and data recording occurred as per the initial consultation. After commencement of treatment, reviews were undertaken every 1 to 2 months until clinical resolution was observed. After achieving clinical resolution, patients were reviewed at 3- to 4-month intervals for the first year, then every 6 months for 1 year, and thereafter annually. Episodes of recurrent disease, as indicated by evidence of active disease on slit-lamp examination or biopsy, were recorded and treated using either further topical MMC, IFN, surgical excision, or a combination thereof. STATISTICAL ANALYSIS:
Univariate and multivariate Cox proportional hazard analyses were used to examine potential factors associated with OSSN recurrence. In cases of bilateral OSSN (n ¼ 8), only the right eye data were included to ensure statistical independence. Factors included in the analyses were patient age and gender, history of previous OSSN treatment (none, MMC interventions, non-MMC interventions), lesion size (6 mm), lesion location (conjunctiva, limbus, cornea), treatment type (MMC, IFN), and treatment duration (MMC, number of cycles; IFN, number of months). For the multivariate analysis, a forward stepwise approach was used (P < .05 for inclusion and P > .10 for exclusion in the model). Kaplan-Meier analysis was used to examine time to OSSN recurrence, and Kaplan-Meier survival curves were compared using the log-rank test. All statistical analyses were performed using SPSS software version 21.0 (IBM Corp, Armonk, New York, USA).
RESULTS A TOTAL OF 168 PATIENTS WHO HAD RECEIVED TREATMENT
with MMC, IFN, or both for OSSN were identified from the 2 pharmacy databases. Of these, 143 eyes of 135 patients (105 men and 30 women) were eligible for inclusion in this study. The reasons for exclusion included follow-up of fewer than 6 months (n ¼ 15), intolerance to either topical medication (n ¼ 6), and for adjunctive treatment in the immediate postoperative period after inadequate excision margin on histologic analysis (n ¼ 12). At commencement of treatment, the mean patient age was 69 years (range, 22 to 91 years). Of the 143 eyes included, 37 (25.9%) were recurrent lesions occurring after previous topical or surgical treatment by other ophthalmologists. All of these lesions as well as another 19 (13.3%) eyes were confirmed by histopathologic examination. The 143 eyes included in the study achieved initial clinical resolution by using only topical agents. Of the 129 eyes treated with MMC, clinical resolution occurred in 102 (79.1%), with a mean treatment of 3.3 cycles (range, 2 to 6 cycles; Table 1). Fewer cycles were required if the patient had undergone previous topical treatment, surgery, or both. The 27 eyes that did not resolve fully with MMC were given topical IFN and subsequently achieved clinical resolution with a mean treatment time of 3.9 months (range, 1 to 8 months). IFN was used as the initial topical treatment in 19 eyes in which the patient either had a history of prior failed treatment with MMC (n ¼ 12) or a poor ocular surface before commencement of treatment (n ¼ 7). Of these 19 eyes given IFN as their initial treatment, clinical VOL. 157, NO. 2
resolution was achieved with a mean time of 5 months (range, 2 to 8 months). Adverse effects occurred in 76 (58.9%) patients using MMC and in 14 (30.4%) patients using IFN. The most common side effects reported were conjunctival hyperemia or irritation (MMC, n ¼ 63 [48.8%]; IFN, n ¼ 13 [28.2%]), followed by localized allergic or toxic reactions (defined as papillary conjunctivitis, lid swelling, or both; MMC, n ¼ 12 [9.3%]) and punctal stenosis (MMC, n ¼ 7 [5.4%]). There was a single case of corneal erosion in each of the MMC and IFN groups. Patients occasionally had more than 1 adverse effect. There were no cases of limbal stem cell deficiency identified. Most side effects were mild and were tolerated by patients. Side effects significant enough to result in cessation of treatment before clinical resolution occurred in 12 (8.4%) of 143 eyes; all were with MMC. However, 11 of these subsequently were treated successfully with topical IFN. During the follow-up period, clinical recurrences were diagnosed in 19 (14.1%) of the 135 patients after topical treatment (Figure 1). Of these 19 patients, 12 patients (12.5%) had no prior treatment (n ¼ 96) and 7 patients (18.0%) previously were treated either topically or surgically (n ¼ 39). Fourteen recurrences (15.1%) were in patients treated only with MMC (n ¼ 93), 4 recurrences (20.0%) were in patients treated with both MMC and IFN (n ¼ 20), and only 1 recurrence (4.6%) was in patients treated only with INF (n ¼ 22). The mean time to recurrence was 17.2 months (range, 4 to 61 months), with 14 patients (73.7%) recurring within a 2-year period. Table 2 summarizes the results of the univariate Cox proportional hazard analysis. There was no significantly greater risk of recurrence associated with lesion size or location, gender, age, treatment duration, or treatment type according to univariate Cox proportional hazard analysis (P > .05). The only factor potentially associated with an increased risk of OSSN recurrence was previous treatment method. Lesions initially treated with surgical excision alone were associated with a greater risk of recurrence (hazard ratio, 2.61; 95% confidence interval, 0.92 to 7.43) that bordered on statistical significance (P ¼ .07). Similarly, Kaplan-Meier analysis revealed that the variables of interest, including lesion size and location, gender, age, treatment duration, and treatment type, did not
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FIGURE 1. Slit-lamp photographs from the right eye of an 83-year-old man. (Left) Primary nasal limbal ocular surface squamous neoplasia (leukoplakic with corkscrew vessels) extending from 2.30 to 5.30 onto the peripheral cornea. (Middle) Appearance of nasal limbal ocular surface squamous neoplasia after 2 cycles of topical mitomycin C over 2 months showing regression. (Right) Recurrence of nasal limbal ocular surface squamous neoplasia from 2.00 to 3.00 at 11 months after regression of the initial lesion.
TABLE 2. Univariate Cox Proportional Hazard Analysis for Ocular Surface Squamous Neoplasia Recurrence Factor
HR
95% CI
P Valuea
Age (y) Gender Male (n ¼ 105) Female (n ¼ 30) Previous treatment None (n ¼ 96) MMC (n ¼ 21) Surgery alone (n ¼ 18) Lesion size (mm) 6 (n ¼ 59) Lesion location Conjunctiva (n ¼ 6) Limbus (n ¼ 98) Cornea (n ¼ 31) Treatment MMC (n ¼ 93) IFN (n ¼ 22) MMC and IFN (n ¼ 20) Treatment duration MMC (cycles) IFN (mos)
1.00
0.94 to 1.04
.70
1.54
0.58 to 4.08
.38
DISCUSSION THE USE OF TOPICAL TREATMENT FOR OSSN HAS BEEN WELL
0.60 2.61
0.13 to 2.70 0.92 to 7.43
.51 .07
0.40 0.94
0.11 to 1.48 0.29 to 2.99
.40 .94
0.49 0.82
0.11 to 2.24 0.17 to 4.12
.36 .81
0.27 1.33
0.04 to 2.02 0.44 to 4.03
.20 .62
0.96 0.46
0.60 to 1.52 0.05 to 4.33
.85 .50
CI ¼ confidence interval; HR ¼ hazard ratio; IFN ¼ interferon alpha-2b; MMC ¼ mitomycin C. a P < .05 considered statistically significant.
significantly influence recurrence of OSSN (P > .05; Table 3). The mean time to recurrence of OSSN was 23.2 6 1.6 months (Figure 2). However, as for the univariate analysis, time to recurrence was influenced by previous treatment method (Figure 3). Post hoc log-rank pairwise comparisons revealed that lesions initially treated using surgery alone had significantly reduced time to recurrence (21.1 6 5.6 months) compared with previous topical treatment with MMC (with or without surgery; 29.6 6 4.7 months; P ¼ .04) and primary OSSN (23.2 6 1.8 months; 290
P ¼ .07). Larger lesions were associated with reduced time to recurrence (6 mm, 21.4 6 2.5 months); however, this trend did not reach statistical significance (P ¼ .22).
documented and confers a number of advantages when compared with surgical excision, including delivery of treatment to the entire ocular surface, thereby treating microscopic disease and subclinical dysplasia, reduced risk of stem cell deficiency from wide surgical excision, reduced patient morbidity, ease of application, and cost efficacy.4,7,8 The traditional surgical approach has limitations, with microscopic evidence of the tumor often extending far beyond the macroscopic edges, and the risk of compromising the ocular surface and limbal stem cells, especially with large tumors and those involving the limbus.2 Surgical excision of OSSN generally was regarded as the gold standard management in the past, because the tumor is confirmed by histopathologic analysis. There are limitations to the use of topical management. Clinically, the experienced physician needs to perform a slit-lamp assessment to diagnose OSSN, although newer diagnostic techniques, including toludine blue and ultra– high-resolution optical coherence tomography, have been reported to aid in the diagnosis.9,10 If there is any uncertainty, impression cytologic analysis or incisional biopsy can improve diagnostic accuracy; however, both are limited to the tissue sampled and may not necessarily be representative of the entire lesion. There is also the potential risk of seeding neoplastic cells into deeper tissue layers with incisional biopsy. It is also difficult to be certain on clinical examination alone regarding the depth of the lesion; however, invasive disease more characteristically is less mobile because of involvement of the underlying sclera. It is possible that early malignant lesions in this series were treated topically with success and no recurrence, but this is not a recommended practice. It is
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TABLE 3. Kaplan-Meier Analysis of Recurrence of Ocular Surface Squamous Neoplasia Mean Time to Recurrence 6 SE Factor
All eyes (n ¼ 135) Age (y) < _67 (n ¼ 59) >67 (n ¼ 76) Sex Male (n ¼ 105) Female (n ¼ 30) Previous treatment None (n ¼ 96) MMC (n ¼ 21) Surgery alone (n ¼ 18) Lesion size (mm) 6 (n ¼ 59) Lesion location Conjunctiva (n ¼ 6) Limbus (n ¼ 98) Cornea (n ¼ 31) Treatment type MMC (n ¼ 93) IFN (n ¼ 22) MMC and IFN (n ¼ 20)
P Value
(mos)
95% CI
(Log-Rank)a
23.2 6 1.6
20.00-26.45
NA
25.8 6 2.4 21.2 6 2.2
21.01-30.61 16.83-25.62
.27
23.2 6 1.9
19.37-27.05
.38
23.3 6 2.9
17.42-29.18
23.2 6 1.8 29.6 6 4.7 21.1 6 5.6
18.74-25.74 19.75-39.39 9.36-32.86
.09
28.8 6 4.9 23.6 6 2.5 21.4 6 2.5
18.41-39.09 18.68-28.49 16.47-26.27
.22
26.3 6 2.7
19.38-33.28
.45
23.2 6 2.0
19.19-27.24
22.7 6 3.1
16.43-28.93
22.7 6 2.0 26.6 6 4.2 22.0 6 3.8
18.71-26.68 17.92-35.26 14.16-9.84
.30
CI ¼ confidence interval; IFN ¼ interferon alpha-2b; MMC ¼ mitomycin C; SE ¼ standard error. a P < .05 considered statistically significant.
likely that malignant lesions would fail topical treatment, resulting in excision and subsequent histologic confirmation. In the current study, for primary OSSN lesions, topical MMC was used as first-line therapy and was changed to IFN if the patient did not respond or experienced intolerable side effects. Despite the observed side effects from MMC, the dosing protocol is shorter and less onerous than that of IFN, as well as being more cost effective. Otherwise in practice, either topical agent can be used to commence treatment, and the patient can be changed to the alternative agent if necessary. The cost-benefit ratio favors this topical approach compared with surgical intervention, which involves doctors’ fees, operating room fees, and consumables, and the cost of loss of income for the patient during postoperative recovery.11 VOL. 157, NO. 2
FIGURE 2. Kaplan-Meier survival curve demonstrating the recurrence of ocular surface squamous neoplasia over time.
The findings from the present study suggest that topical treatment is effective for both primary and recurrent OSSN. A combination of MMC and IFN can be used; however, surgical excision is still required if the lesion does not resolve completely. Bahrami and associates found only 1 recurrence among 153 eyes after a minimum of follow-up of 12 months using an excision with or without cryotherapy followed by either a course of topical 5-fluorouracil 1% 4 times daily for 2 weeks or topical MMC 0.04% 4 times daily for 2 to 3 1-week cycles.12 Lesion size and location, gender, age, treatment duration, or a combination thereof were not identified as predictive factors for recurrence of OSSN after topical therapy with MMC, IFN, or both in the present study. This suggests that topical treatment can be used for presumed noninvasive OSSN lesions over a range of patient presentations. The finding that recurrent OSSN after previous surgical excision has a tendency to increase the risk of recurrence after topical therapy warrants further consideration. A possible explanation may be that surgical excision disrupts the natural tissue barriers to neoplastic change. Further study is needed to confirm this hypothesis. True recurrence of a lesion is difficult to determine with certainty, as opposed to inadequate treatment with regrowth of residual tumor cells. The lesions in this study were examined clinically and were determined to have resolved; however, histologic confirmation would be more ideal. In practice, repeat biopsy of a resolved region generally is not performed unless there is clinical evidence of recurrence. The observation of recurrence also depends on duration of follow-up, and it is possible more lesions eventually will recur if followed up for a longer period.
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FIGURE 3. Kaplan-Meier survival curves based on previous treatment of ocular surface squamous neoplasia. MMC [ mitomycin C.
Most recurrences (73.7%) occurred within 24 months of follow-up, indicating that follow-up should be more frequent in this period after cessation of treatment. Other ways to enhance topical therapy have been suggested. Shields and associates reported a series of 81 tumors in 80 patients treated with topical IFN, IFN injection, or both.13 They reported resolution in more than 95% of patients treated for primary, recurrent, and postsurgical lesions. Injection of IFN (10 MIU/mL) was performed by a 30-gauge needle to the sublesional and perilesional region, avoiding direct injection of the tumor. This method was not used in the current study, but would be a useful option particularly for more extensive lesions. Krilis and associates used topical IFN in combination with retinoic acid 0.01% once every second day to enhance therapy by reversing the upregulation of matrix metalloproteinases, thereby inhibiting tumor growth and
reducing rates of treatment failure.14 Treatment was continued for 12 months after resolution. Although complete clinical resolution of 87 (97.8%) of 89 eyes was achieved, further study is needed to prove whether this combination and duration of therapy is advantageous. Other studies also have investigated the use of anti– vascular endothelial growth factor agents in the treatment of OSSN.15 Topical 5-fluorouracil 1% has been shown to be a useful topical agent with a safety profile confirmed by confocal microscopy.16 In conclusion, the findings of this study show that topical therapy can be used as first-line therapy for both primary and recurrent clinically diagnosed noninvasive OSSN. This study suggests low rates of recurrence with topical therapy, comparable with those of surgical excision with cryotherapy, with the benefit of reducing the cost and risk of complications.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Design of study (J.B., J.P., G.A.L.); Conduct of study (J.B., J.P., G.A.L.); Collection (J.B., J.P., G.A.L.), management (G.A.L.), analysis (J.B., J.P., G.A.L., S.J.V.), and interpretation (J.B., J.P., G.A.L., S.J.V.) of data; and Preparation, review, or approval of manuscript (J.B., J.P., G.A.L., S.J.V., L.W.H.).
REFERENCES 1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39(6):429–450. 2. Kiire CA, Srinivasan S, Karp CL. Ocular surface squamous neoplasia. Int Ophthalmol Clin 2010;50(3):35–46. 3. Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and the necessity for long-term follow-up in
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corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997;104(3):485–492. 4. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology 2007;114(5):976–982. 5. Buus DR, Tse DT, Folberg R, Buuns DR. Microscopically controlled excision of conjunctival squamous cell carcinoma. Am J Opthhalmol 1994;117(1):97–102.
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6. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology 2012;119(10):1974–1981. 7. Sepulveda R, Pe’er J, Midena E, Seregard S, Dua HS, Singh AD. Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2010;94(5): 532–535. 8. Kim JW, Abramson DH. Topical treatment options for conjunctival neoplasms. Clin Ophthalmol 2008;2(3): 503–515. 9. Romero IL, Barros Jde N, Martins MC, Ballalai PL. The use of 1% toluidine blue eye drops in the diagnosis of ocular surface squamous neoplasia. Cornea 2013;32(1):36–39. 10. Kieval JZ, Karp CL, Abou Shousha M, et al. Ultra-high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology 2012;119(3):481–486. 11. Kim HJ, Shields CL, Shah SU, Kaliki S, Lally SE. Giant ocular surface squamous neoplasia managed with interferon alpha-2b as immunotherapy or immunoreduction. Ophthalmology 2012;119(5):938–944.
12. Bahrami B, Greenwell T, Muecke JS. Long-term outcomes after adjunctive topical 5-fluorouracil or mitomycin C for the treatment of surgically excised localised ocular surface squamous neoplasia. Clin Experiment Ophthalmol. 2013 Aug 8. doi: 10.1111/ceo.12184. [Epub ahead of print]. 13. Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea 2013;32(3):248–256. 14. Krilis M, Tsang H, Coroneo M. Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow-up. Ophthalmology 2012;119(10):1969–1973. 15. Finger PT, Chin KJ. Refractory squamous cell carcinoma of the conjunctiva treated with subconjunctival ranibizumab (Lucentis): a two-year study. Ophthal Plast Reconstr Surg 2012;28(2):85–89. 16. Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol 2011;95(3):355–359.
REPORTING VISUAL ACUITIES The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities is provided to the readers as an aid to interpret visual acuity findings in familiar units.
Table of Equivalent Visual Acuity Measurements Snellen Visual Acuities 4 Meters
6 Meters
20 Feet
Decimal Fraction
LogMAR
4/40 4/32 4/25 4/20 4/16 4/12.6 4/10 4/8 4/6.3 4/5 4/4 4/3.2 4/2.5 4/2
6/60 6/48 6/38 6/30 6/24 6/20 6/15 6/12 6/10 6/7.5 6/6 6/5 6/3.75 6/3
20/200 20/160 20/125 20/100 20/80 20/63 20/50 20/40 20/32 20/25 20/20 20/16 20/12.5 20/10
0.10 0.125 0.16 0.20 0.25 0.32 0.40 0.50 0.63 0.80 1.00 1.25 1.60 2.00
þ1.0 þ0.9 þ0.8 þ0.7 þ0.6 þ0.5 þ0.4 þ0.3 þ0.2 þ0.1 0.0 0.1 0.2 0.3
From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.
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Biosketch Doctor Jenna Besley is from Brisbane, Australia with a Bachelor of Science, Bachelor of Medicine and Surgery and completing a Masters of Medicine in Ophthalmic Science. She has worked at City Eye Centre in Brisbane as a preclinical fellow and currently is a non-training registrar at John Hunter Hospital in Newcastle, New South Wales, Australia. She has a special interest in health advocacy particularly in the areas of rural and indigenous health.
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Biosketch Associate Professor Graham Lee is from Brisbane, Australia with a Bachelor of Medicine and Surgery, a Master of Medical Science, a Fellowship of the Royal Australian and New Zealand College of Ophthalmology and a Doctorate of Medicine. He has undertaken a Glaucoma Fellowship at Birmingham and Midlands Eye Centre, Birmingham and a Cataract, Cornea and Refractive Fellowship at Moorfields Eye Hospital in London. He is active in teaching with particular interest in developing countries.
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To determine the rate of recurrence and associated risk factors after the use of mitomycin C (MMC), interferon alpha-2b, or both for management of noninvasive ocular surface squamous neoplasia (OSSN). DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Clinical practice setting of 135 patients treated consecutively with topical MMC (0.4 mg/mL), interferon alpha-2b (1 million units/mL), or both for OSSN observed for clinical recurrence. RESULTS: Clinical recurrences were diagnosed in 19 (14.1%) of 135 eyes after topical treatment. The mean time to recurrence was 17.2 months (range, 4 to 61 months), with 14 eyes (73.7%) recurring within a 2-year period. There was no greater risk of recurrence identified for variables including lesion size, lesion location, gender, age, treatment type, or treatment duration. Post hoc log-rank pairwise comparisons revealed that lesions initially treated using surgery alone had significantly reduced time to recurrence (21.1 ± 5.6 months) compared with previous topical treatment with MMC (with or without surgery; 29.6 ± 4.7 months; P [ .04) and primary OSSN (23.2 ± 1.8 months; P [ .09). CONCLUSIONS: Topical MMC and interferon alpha-2b are an effective treatment method for a wide range of noninvasive OSSNs. Topical therapy avoids the morbidity of excisional surgery with equivalent or reduced recurrence rates and should be considered as primary therapy. (Am J Ophthalmol 2014;157:287–293. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Oct 21, 2013. From the Department of Ophthalmology, City Eye Centre, Brisbane, Australia (J.B., J.P., G.A.L.); the Department of Ophthalmology, University of Queensland, Brisbane, Australia (J.P., G.A.L., L.W.H.); the Department of Ophthalmology, Royal Brisbane Hospital, Brisbane, Australia (G.A.L.); the Department of Ophthalmology, The Australian Pterygium Centre, Brisbane, Australia (L.W.H.); the Department of Ophthalmology, Queensland Eye Institute, Brisbane, Australia (L.W.H.); and the School of Optometry and Vision Science, Queensland University of Technology, Kelvin Grove, Australia (S.J.V.). Inquiries to Graham A. Lee, City Eye Centre, 10/135 Wickham Terrace, Brisbane, Queensland 4000, Australia; e-mail: eye@cityeye. com.au 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.012
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2014 BY
O
CULAR SURFACE SQUAMOUS NEOPLASIA (OSSN)
encompasses a spectrum of lesions arising from the squamous cells of the conjunctiva, cornea, or both.1 Excessive exposure to ultraviolet B radiation is the major etiologic factor; however, other causes, such as human papillomavirus types 16 and 18 and HIV seropositivity, also have been implicated.1,2 OSSN is described as a relatively low-grade malignancy because invasive disease is uncommon and tends to be preceded by dysplasia and carcinoma in situ.1 However, a lack of appropriate and effective treatment for OSSN can result in malignant change followed by local invasion and, rarely, metastasis. Surgical excision with adequate margins and adjunctive cryotherapy is a well-established treatment for OSSN, although this is an invasive option with numerous disadvantages. Tabin and associates described high recurrence rates after surgical excision (33% at 10 years despite histologically clear surgical margins).3 Evidence suggests that the microscopic changes associated with OSSN extend beyond the macroscopic margin; thus, surgical excision to achieve clear margins is difficult.4 Techniques to examine tumor margins and conserve normal tissue such as Moh micrographic surgery have been adapted for oculoplastic tumor work; however, frozen sections are challenging to perform on small fragile corneal or conjunctival specimens.5 Additionally, because of the multifocal nature of OSSN, surgical excision results in wide collateral damage to adjacent areas of normal epithelium, including the potential for limbal stem cell deficiency and visually disturbing corneal scarring.4 A recent study by Galor and associates examined the rates of recurrence after surgical excision using various techniques and found them to be 10% at 1 year and 21% at 5 years.6 The authors identified tarsal involvement and positive pathologic margins as the strongest predictors of clinical recurrence after surgical excision of OSSN lesions. High-grade lesions, large lesions, and a previous patient history of OSSN were associated with an increased risk of tumor recurrence. The mean time to clinical recurrence after surgical excision was 2.5 years. The purpose of this study was to identify predictive factors of OSSN recurrence after topical treatment of noninvasive OSSN using a large, retrospective case series. The study examined the rates of recurrence of OSSN after the use of topical treatment for both primary therapy and for
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the treatment of recurrences using mitomycin C (MMC), interferon alpha-2b (IFN), or both. Identification of risks for recurrence potentially may allow for tailored management plans, with the aim of improving treatment success.
METHODS IN THIS RETROSPECTIVE, NONCOMPARATIVE, INTERVEN-
tional case series study, clinical data of 143 eyes of 135 patients diagnosed with OSSN were reviewed. Approval to conduct this study was obtained prospectively from the Royal Australian and New Zealand College of Ophthalmologists Human Research Ethics Committee (study no. 29.11). The National Health and Medical Research Council guidelines were followed, and it adhered to the tenets of the Declaration of Helsinki. Database information allowed identification of all prescriptions for MMC or IFN dispensed consecutively by 2 oncology pharmacies: the Royal Brisbane and Women’s Hospital, a tertiary referral hospital in Brisbane, Queensland, Australia, and Custom Care Compounding Pharmacy in Dural, New South Wales, Australia. Eligible patients were those whose first prescription was dispensed between December 2001 and December 2012. Of these patients, those who were treated by a single ophthalmologist (G.A.L.) were chosen as candidates for inclusion in the study. This was to ensure uniformity in treatment regimen and clinical examination techniques. OSSN was diagnosed principally by clinical examination, but in some equivocal cases, by histology. All cases were primary or recurrent noninvasive lesions. Invasive lesions were excluded on the basis of tethering to the underlying sclera on indirect palpation of the lesion through the lid. For those patients with recurrent disease, previous treatment methods were recorded. Treatment with MMC or IFN continued until either clinical resolution was achieved or the treatment was deemed to have failed. Treatment failure was defined as lack of response after 3 to 4 cycles of treatment with MMC, failure to achieve complete clinical resolution after up to 6 months of treatment with IFN, or both. Patients with fewer than 6 months of follow-up after clinical resolution were excluded from this study. All patients underwent a comprehensive ophthalmic examination at the commencement of treatment and at all follow-up visits, including uncorrected and corrected visual acuity, intraocular pressure measurement, and slitlamp examination with photography. The diagnosis of OSSN was made by a single ophthalmologist experienced in examining ocular tumors (G.A.L.). In the primary cases, this was performed clinically, relying on the characteristic features of OSSN: gelatinous, papilliform, or leukoplakic lesion with characteristic tufted, superficial, so-called corkscrew vessels. This avoided more invasive incisional 288
biopsy; however, in cases where the clinical diagnosis was uncertain, a scraping or biopsy sample was obtained for histologic diagnosis. Impression cytologic analysis was not available during the course of the study. The location and dimensions of the lesion were recorded at the commencement of treatment, with appropriate measurements obtained using the slit lamp. For purposes of data analysis, the lesions were grouped according to the maximal basal diameter (in millimeters). The MMC and IFN eye drops used in this study were prepared extemporaneously by the oncology pharmacy of the Royal Brisbane and Women’s Hospital, Brisbane, Australia (2001 through 2009) and the Custom Care Compounding Pharmacy, Sydney, Australia (2010 through 2012) under cytotoxic laminar flow conditions. The MMC (Kyowa Kirin, Berkshire, United Kingdom) was prepared at a concentration of 0.04% by reconstituting 2 mg powder with 5 mL of 0.9% saline, filtered and stored in a sterile plastic bottle. The IFN was prepared at a concentration of 1 million IU/mL by diluting 0.67 mL of 18M IU/1.2 mL injectable recombinant IFN (Intron A; Merck & Co., Inc., Whitehouse Station, New Jersey, USA) with 0.9% saline up to 10 mL, filtered and stored in 3 sterile plastic bottles. All side effects reported by the patients or observed during clinical examination were documented. Patients were administered a regimen of MMC 0.04% 4 times daily for 1 week, followed by 3 weeks off treatment. This treatment cycle was repeated until an end point was reached. If necessary, patients were prescribed lubricant eye drops and dexamethasone 1% 4 times daily to resolve minor redness or irritation. Patients were administered IFN 1 million IU/mL 4 times daily if previous treatment with MMC had failed or if they were unable to tolerate MMC as a result of side effects. Again, this treatment was continued until an end point was reached. Patients who failed to respond to topical treatment underwent surgical excision. At each follow-up visit, ophthalmic examination and data recording occurred as per the initial consultation. After commencement of treatment, reviews were undertaken every 1 to 2 months until clinical resolution was observed. After achieving clinical resolution, patients were reviewed at 3- to 4-month intervals for the first year, then every 6 months for 1 year, and thereafter annually. Episodes of recurrent disease, as indicated by evidence of active disease on slit-lamp examination or biopsy, were recorded and treated using either further topical MMC, IFN, surgical excision, or a combination thereof. STATISTICAL ANALYSIS:
Univariate and multivariate Cox proportional hazard analyses were used to examine potential factors associated with OSSN recurrence. In cases of bilateral OSSN (n ¼ 8), only the right eye data were included to ensure statistical independence. Factors included in the analyses were patient age and gender, history of previous OSSN treatment (none, MMC interventions, non-MMC interventions), lesion size (6 mm), lesion location (conjunctiva, limbus, cornea), treatment type (MMC, IFN), and treatment duration (MMC, number of cycles; IFN, number of months). For the multivariate analysis, a forward stepwise approach was used (P < .05 for inclusion and P > .10 for exclusion in the model). Kaplan-Meier analysis was used to examine time to OSSN recurrence, and Kaplan-Meier survival curves were compared using the log-rank test. All statistical analyses were performed using SPSS software version 21.0 (IBM Corp, Armonk, New York, USA).
RESULTS A TOTAL OF 168 PATIENTS WHO HAD RECEIVED TREATMENT
with MMC, IFN, or both for OSSN were identified from the 2 pharmacy databases. Of these, 143 eyes of 135 patients (105 men and 30 women) were eligible for inclusion in this study. The reasons for exclusion included follow-up of fewer than 6 months (n ¼ 15), intolerance to either topical medication (n ¼ 6), and for adjunctive treatment in the immediate postoperative period after inadequate excision margin on histologic analysis (n ¼ 12). At commencement of treatment, the mean patient age was 69 years (range, 22 to 91 years). Of the 143 eyes included, 37 (25.9%) were recurrent lesions occurring after previous topical or surgical treatment by other ophthalmologists. All of these lesions as well as another 19 (13.3%) eyes were confirmed by histopathologic examination. The 143 eyes included in the study achieved initial clinical resolution by using only topical agents. Of the 129 eyes treated with MMC, clinical resolution occurred in 102 (79.1%), with a mean treatment of 3.3 cycles (range, 2 to 6 cycles; Table 1). Fewer cycles were required if the patient had undergone previous topical treatment, surgery, or both. The 27 eyes that did not resolve fully with MMC were given topical IFN and subsequently achieved clinical resolution with a mean treatment time of 3.9 months (range, 1 to 8 months). IFN was used as the initial topical treatment in 19 eyes in which the patient either had a history of prior failed treatment with MMC (n ¼ 12) or a poor ocular surface before commencement of treatment (n ¼ 7). Of these 19 eyes given IFN as their initial treatment, clinical VOL. 157, NO. 2
resolution was achieved with a mean time of 5 months (range, 2 to 8 months). Adverse effects occurred in 76 (58.9%) patients using MMC and in 14 (30.4%) patients using IFN. The most common side effects reported were conjunctival hyperemia or irritation (MMC, n ¼ 63 [48.8%]; IFN, n ¼ 13 [28.2%]), followed by localized allergic or toxic reactions (defined as papillary conjunctivitis, lid swelling, or both; MMC, n ¼ 12 [9.3%]) and punctal stenosis (MMC, n ¼ 7 [5.4%]). There was a single case of corneal erosion in each of the MMC and IFN groups. Patients occasionally had more than 1 adverse effect. There were no cases of limbal stem cell deficiency identified. Most side effects were mild and were tolerated by patients. Side effects significant enough to result in cessation of treatment before clinical resolution occurred in 12 (8.4%) of 143 eyes; all were with MMC. However, 11 of these subsequently were treated successfully with topical IFN. During the follow-up period, clinical recurrences were diagnosed in 19 (14.1%) of the 135 patients after topical treatment (Figure 1). Of these 19 patients, 12 patients (12.5%) had no prior treatment (n ¼ 96) and 7 patients (18.0%) previously were treated either topically or surgically (n ¼ 39). Fourteen recurrences (15.1%) were in patients treated only with MMC (n ¼ 93), 4 recurrences (20.0%) were in patients treated with both MMC and IFN (n ¼ 20), and only 1 recurrence (4.6%) was in patients treated only with INF (n ¼ 22). The mean time to recurrence was 17.2 months (range, 4 to 61 months), with 14 patients (73.7%) recurring within a 2-year period. Table 2 summarizes the results of the univariate Cox proportional hazard analysis. There was no significantly greater risk of recurrence associated with lesion size or location, gender, age, treatment duration, or treatment type according to univariate Cox proportional hazard analysis (P > .05). The only factor potentially associated with an increased risk of OSSN recurrence was previous treatment method. Lesions initially treated with surgical excision alone were associated with a greater risk of recurrence (hazard ratio, 2.61; 95% confidence interval, 0.92 to 7.43) that bordered on statistical significance (P ¼ .07). Similarly, Kaplan-Meier analysis revealed that the variables of interest, including lesion size and location, gender, age, treatment duration, and treatment type, did not
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FIGURE 1. Slit-lamp photographs from the right eye of an 83-year-old man. (Left) Primary nasal limbal ocular surface squamous neoplasia (leukoplakic with corkscrew vessels) extending from 2.30 to 5.30 onto the peripheral cornea. (Middle) Appearance of nasal limbal ocular surface squamous neoplasia after 2 cycles of topical mitomycin C over 2 months showing regression. (Right) Recurrence of nasal limbal ocular surface squamous neoplasia from 2.00 to 3.00 at 11 months after regression of the initial lesion.
TABLE 2. Univariate Cox Proportional Hazard Analysis for Ocular Surface Squamous Neoplasia Recurrence Factor
HR
95% CI
P Valuea
Age (y) Gender Male (n ¼ 105) Female (n ¼ 30) Previous treatment None (n ¼ 96) MMC (n ¼ 21) Surgery alone (n ¼ 18) Lesion size (mm) 6 (n ¼ 59) Lesion location Conjunctiva (n ¼ 6) Limbus (n ¼ 98) Cornea (n ¼ 31) Treatment MMC (n ¼ 93) IFN (n ¼ 22) MMC and IFN (n ¼ 20) Treatment duration MMC (cycles) IFN (mos)
1.00
0.94 to 1.04
.70
1.54
0.58 to 4.08
.38
DISCUSSION THE USE OF TOPICAL TREATMENT FOR OSSN HAS BEEN WELL
0.60 2.61
0.13 to 2.70 0.92 to 7.43
.51 .07
0.40 0.94
0.11 to 1.48 0.29 to 2.99
.40 .94
0.49 0.82
0.11 to 2.24 0.17 to 4.12
.36 .81
0.27 1.33
0.04 to 2.02 0.44 to 4.03
.20 .62
0.96 0.46
0.60 to 1.52 0.05 to 4.33
.85 .50
CI ¼ confidence interval; HR ¼ hazard ratio; IFN ¼ interferon alpha-2b; MMC ¼ mitomycin C. a P < .05 considered statistically significant.
significantly influence recurrence of OSSN (P > .05; Table 3). The mean time to recurrence of OSSN was 23.2 6 1.6 months (Figure 2). However, as for the univariate analysis, time to recurrence was influenced by previous treatment method (Figure 3). Post hoc log-rank pairwise comparisons revealed that lesions initially treated using surgery alone had significantly reduced time to recurrence (21.1 6 5.6 months) compared with previous topical treatment with MMC (with or without surgery; 29.6 6 4.7 months; P ¼ .04) and primary OSSN (23.2 6 1.8 months; 290
P ¼ .07). Larger lesions were associated with reduced time to recurrence (6 mm, 21.4 6 2.5 months); however, this trend did not reach statistical significance (P ¼ .22).
documented and confers a number of advantages when compared with surgical excision, including delivery of treatment to the entire ocular surface, thereby treating microscopic disease and subclinical dysplasia, reduced risk of stem cell deficiency from wide surgical excision, reduced patient morbidity, ease of application, and cost efficacy.4,7,8 The traditional surgical approach has limitations, with microscopic evidence of the tumor often extending far beyond the macroscopic edges, and the risk of compromising the ocular surface and limbal stem cells, especially with large tumors and those involving the limbus.2 Surgical excision of OSSN generally was regarded as the gold standard management in the past, because the tumor is confirmed by histopathologic analysis. There are limitations to the use of topical management. Clinically, the experienced physician needs to perform a slit-lamp assessment to diagnose OSSN, although newer diagnostic techniques, including toludine blue and ultra– high-resolution optical coherence tomography, have been reported to aid in the diagnosis.9,10 If there is any uncertainty, impression cytologic analysis or incisional biopsy can improve diagnostic accuracy; however, both are limited to the tissue sampled and may not necessarily be representative of the entire lesion. There is also the potential risk of seeding neoplastic cells into deeper tissue layers with incisional biopsy. It is also difficult to be certain on clinical examination alone regarding the depth of the lesion; however, invasive disease more characteristically is less mobile because of involvement of the underlying sclera. It is possible that early malignant lesions in this series were treated topically with success and no recurrence, but this is not a recommended practice. It is
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TABLE 3. Kaplan-Meier Analysis of Recurrence of Ocular Surface Squamous Neoplasia Mean Time to Recurrence 6 SE Factor
All eyes (n ¼ 135) Age (y) < _67 (n ¼ 59) >67 (n ¼ 76) Sex Male (n ¼ 105) Female (n ¼ 30) Previous treatment None (n ¼ 96) MMC (n ¼ 21) Surgery alone (n ¼ 18) Lesion size (mm) 6 (n ¼ 59) Lesion location Conjunctiva (n ¼ 6) Limbus (n ¼ 98) Cornea (n ¼ 31) Treatment type MMC (n ¼ 93) IFN (n ¼ 22) MMC and IFN (n ¼ 20)
P Value
(mos)
95% CI
(Log-Rank)a
23.2 6 1.6
20.00-26.45
NA
25.8 6 2.4 21.2 6 2.2
21.01-30.61 16.83-25.62
.27
23.2 6 1.9
19.37-27.05
.38
23.3 6 2.9
17.42-29.18
23.2 6 1.8 29.6 6 4.7 21.1 6 5.6
18.74-25.74 19.75-39.39 9.36-32.86
.09
28.8 6 4.9 23.6 6 2.5 21.4 6 2.5
18.41-39.09 18.68-28.49 16.47-26.27
.22
26.3 6 2.7
19.38-33.28
.45
23.2 6 2.0
19.19-27.24
22.7 6 3.1
16.43-28.93
22.7 6 2.0 26.6 6 4.2 22.0 6 3.8
18.71-26.68 17.92-35.26 14.16-9.84
.30
CI ¼ confidence interval; IFN ¼ interferon alpha-2b; MMC ¼ mitomycin C; SE ¼ standard error. a P < .05 considered statistically significant.
likely that malignant lesions would fail topical treatment, resulting in excision and subsequent histologic confirmation. In the current study, for primary OSSN lesions, topical MMC was used as first-line therapy and was changed to IFN if the patient did not respond or experienced intolerable side effects. Despite the observed side effects from MMC, the dosing protocol is shorter and less onerous than that of IFN, as well as being more cost effective. Otherwise in practice, either topical agent can be used to commence treatment, and the patient can be changed to the alternative agent if necessary. The cost-benefit ratio favors this topical approach compared with surgical intervention, which involves doctors’ fees, operating room fees, and consumables, and the cost of loss of income for the patient during postoperative recovery.11 VOL. 157, NO. 2
FIGURE 2. Kaplan-Meier survival curve demonstrating the recurrence of ocular surface squamous neoplasia over time.
The findings from the present study suggest that topical treatment is effective for both primary and recurrent OSSN. A combination of MMC and IFN can be used; however, surgical excision is still required if the lesion does not resolve completely. Bahrami and associates found only 1 recurrence among 153 eyes after a minimum of follow-up of 12 months using an excision with or without cryotherapy followed by either a course of topical 5-fluorouracil 1% 4 times daily for 2 weeks or topical MMC 0.04% 4 times daily for 2 to 3 1-week cycles.12 Lesion size and location, gender, age, treatment duration, or a combination thereof were not identified as predictive factors for recurrence of OSSN after topical therapy with MMC, IFN, or both in the present study. This suggests that topical treatment can be used for presumed noninvasive OSSN lesions over a range of patient presentations. The finding that recurrent OSSN after previous surgical excision has a tendency to increase the risk of recurrence after topical therapy warrants further consideration. A possible explanation may be that surgical excision disrupts the natural tissue barriers to neoplastic change. Further study is needed to confirm this hypothesis. True recurrence of a lesion is difficult to determine with certainty, as opposed to inadequate treatment with regrowth of residual tumor cells. The lesions in this study were examined clinically and were determined to have resolved; however, histologic confirmation would be more ideal. In practice, repeat biopsy of a resolved region generally is not performed unless there is clinical evidence of recurrence. The observation of recurrence also depends on duration of follow-up, and it is possible more lesions eventually will recur if followed up for a longer period.
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FIGURE 3. Kaplan-Meier survival curves based on previous treatment of ocular surface squamous neoplasia. MMC [ mitomycin C.
Most recurrences (73.7%) occurred within 24 months of follow-up, indicating that follow-up should be more frequent in this period after cessation of treatment. Other ways to enhance topical therapy have been suggested. Shields and associates reported a series of 81 tumors in 80 patients treated with topical IFN, IFN injection, or both.13 They reported resolution in more than 95% of patients treated for primary, recurrent, and postsurgical lesions. Injection of IFN (10 MIU/mL) was performed by a 30-gauge needle to the sublesional and perilesional region, avoiding direct injection of the tumor. This method was not used in the current study, but would be a useful option particularly for more extensive lesions. Krilis and associates used topical IFN in combination with retinoic acid 0.01% once every second day to enhance therapy by reversing the upregulation of matrix metalloproteinases, thereby inhibiting tumor growth and
reducing rates of treatment failure.14 Treatment was continued for 12 months after resolution. Although complete clinical resolution of 87 (97.8%) of 89 eyes was achieved, further study is needed to prove whether this combination and duration of therapy is advantageous. Other studies also have investigated the use of anti– vascular endothelial growth factor agents in the treatment of OSSN.15 Topical 5-fluorouracil 1% has been shown to be a useful topical agent with a safety profile confirmed by confocal microscopy.16 In conclusion, the findings of this study show that topical therapy can be used as first-line therapy for both primary and recurrent clinically diagnosed noninvasive OSSN. This study suggests low rates of recurrence with topical therapy, comparable with those of surgical excision with cryotherapy, with the benefit of reducing the cost and risk of complications.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Design of study (J.B., J.P., G.A.L.); Conduct of study (J.B., J.P., G.A.L.); Collection (J.B., J.P., G.A.L.), management (G.A.L.), analysis (J.B., J.P., G.A.L., S.J.V.), and interpretation (J.B., J.P., G.A.L., S.J.V.) of data; and Preparation, review, or approval of manuscript (J.B., J.P., G.A.L., S.J.V., L.W.H.).
REFERENCES 1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39(6):429–450. 2. Kiire CA, Srinivasan S, Karp CL. Ocular surface squamous neoplasia. Int Ophthalmol Clin 2010;50(3):35–46. 3. Tabin G, Levin S, Snibson G, Loughnan M, Taylor H. Late recurrences and the necessity for long-term follow-up in
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corneal and conjunctival intraepithelial neoplasia. Ophthalmology 1997;104(3):485–492. 4. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology 2007;114(5):976–982. 5. Buus DR, Tse DT, Folberg R, Buuns DR. Microscopically controlled excision of conjunctival squamous cell carcinoma. Am J Opthhalmol 1994;117(1):97–102.
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6. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology 2012;119(10):1974–1981. 7. Sepulveda R, Pe’er J, Midena E, Seregard S, Dua HS, Singh AD. Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2010;94(5): 532–535. 8. Kim JW, Abramson DH. Topical treatment options for conjunctival neoplasms. Clin Ophthalmol 2008;2(3): 503–515. 9. Romero IL, Barros Jde N, Martins MC, Ballalai PL. The use of 1% toluidine blue eye drops in the diagnosis of ocular surface squamous neoplasia. Cornea 2013;32(1):36–39. 10. Kieval JZ, Karp CL, Abou Shousha M, et al. Ultra-high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology 2012;119(3):481–486. 11. Kim HJ, Shields CL, Shah SU, Kaliki S, Lally SE. Giant ocular surface squamous neoplasia managed with interferon alpha-2b as immunotherapy or immunoreduction. Ophthalmology 2012;119(5):938–944.
12. Bahrami B, Greenwell T, Muecke JS. Long-term outcomes after adjunctive topical 5-fluorouracil or mitomycin C for the treatment of surgically excised localised ocular surface squamous neoplasia. Clin Experiment Ophthalmol. 2013 Aug 8. doi: 10.1111/ceo.12184. [Epub ahead of print]. 13. Shields CL, Kaliki S, Kim HJ, et al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on Cancer classification. Cornea 2013;32(3):248–256. 14. Krilis M, Tsang H, Coroneo M. Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow-up. Ophthalmology 2012;119(10):1969–1973. 15. Finger PT, Chin KJ. Refractory squamous cell carcinoma of the conjunctiva treated with subconjunctival ranibizumab (Lucentis): a two-year study. Ophthal Plast Reconstr Surg 2012;28(2):85–89. 16. Parrozzani R, Lazzarini D, Alemany-Rubio E, Urban F, Midena E. Topical 1% 5-fluorouracil in ocular surface squamous neoplasia: a long-term safety study. Br J Ophthalmol 2011;95(3):355–359.
REPORTING VISUAL ACUITIES The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities is provided to the readers as an aid to interpret visual acuity findings in familiar units.
Table of Equivalent Visual Acuity Measurements Snellen Visual Acuities 4 Meters
6 Meters
20 Feet
Decimal Fraction
LogMAR
4/40 4/32 4/25 4/20 4/16 4/12.6 4/10 4/8 4/6.3 4/5 4/4 4/3.2 4/2.5 4/2
6/60 6/48 6/38 6/30 6/24 6/20 6/15 6/12 6/10 6/7.5 6/6 6/5 6/3.75 6/3
20/200 20/160 20/125 20/100 20/80 20/63 20/50 20/40 20/32 20/25 20/20 20/16 20/12.5 20/10
0.10 0.125 0.16 0.20 0.25 0.32 0.40 0.50 0.63 0.80 1.00 1.25 1.60 2.00
þ1.0 þ0.9 þ0.8 þ0.7 þ0.6 þ0.5 þ0.4 þ0.3 þ0.2 þ0.1 0.0 0.1 0.2 0.3
From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.
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Biosketch Doctor Jenna Besley is from Brisbane, Australia with a Bachelor of Science, Bachelor of Medicine and Surgery and completing a Masters of Medicine in Ophthalmic Science. She has worked at City Eye Centre in Brisbane as a preclinical fellow and currently is a non-training registrar at John Hunter Hospital in Newcastle, New South Wales, Australia. She has a special interest in health advocacy particularly in the areas of rural and indigenous health.
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Biosketch Associate Professor Graham Lee is from Brisbane, Australia with a Bachelor of Medicine and Surgery, a Master of Medical Science, a Fellowship of the Royal Australian and New Zealand College of Ophthalmology and a Doctorate of Medicine. He has undertaken a Glaucoma Fellowship at Birmingham and Midlands Eye Centre, Birmingham and a Cataract, Cornea and Refractive Fellowship at Moorfields Eye Hospital in London. He is active in teaching with particular interest in developing countries.
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