ORIGINAL CLINICAL STUDY
Topical Interferon >-2b as a Single Therapy for Primary Ocular Surface Squamous Neoplasia Rakhi Kusumesh, MS,* Anita Ambastha, MS,* Bibhuti Sinha, MS,* and Rajiv Kumar, MD*
Purpose: The aim of this study was to evaluate the efficacy and safety of topical interferon >-2b (IFN>2b) as a single therapy for primary ocular surface squamous neoplasia (OSSN). Methods: Medical records of 24 eyes of 24 patients with primary OSSN were reviewed retrospectively. The diagnosis of OSSN was primarily based on the slit-lamp examination. All cases were treated with topical IFN>2b (1 million IU/mL) 4 times daily. The duration of treatment, tumor response, adverse effects, and number of vials of topical IFN>2b were noted. Complete response was defined as total disappearance of lesions. Results: The complete remission of the tumor was observed in 22 patients (91.6%). Two patients (8.3%) did not respond to the treatment. The mean age was 62.44 T 13.65 years (range, 50Y92 years). The mean follow-up period was 18.81 T 3.81 months (range, 14Y22 months). The median greatest linear dimension was 6 mm (range, 5.2Y12 mm). In all successful remissions, the median time to lesion resolution was 3.25 months. Adverse effects of topical IFN>2b included spontaneous intratumoral bleeding after 3 weeks of topical therapy in 1 patient. No long-term complication or recurrence was found at the end of the follow-up period. Conclusions: Topical IFN>2b is effective and safe as a single therapy in the management of primary OSSN with minimal self-limited adverse effects. It may provide the least invasive way of treating OSSN. Key Words: tumor, OSSN, topical, interferon >-2b, intratumoral bleeding (Asia Pac J Ophthalmol 2015;4: 279Y282)
O
cular surface squamous neoplasia (OSSN) is a spectrum of malignancy that includes intraepithelial dysplasia, carcinoma in situ (CIN) of the conjunctiva and cornea, and invasive squamous cell carcinoma (SCC). Risk factors for this disease are ultraviolet light exposure, petroleum products, heavy cigarette smoking, human papillomavirus infection, and human immunodeficiency virus infection.1Y5 Surgical excision with adjunctive cryotherapy was previously considered the treatment of choice for OSSN.5Y7 However, evidence suggests that microscopic signs of OSSN extend far beyond the macroscopic edges of the tumors, resulting in a relatively high risk of OSSN recurrence after surgery.8,9 Medical treatment alone or as an adjuvant has been used increasingly for these tumors. Possible advantages of medical therapy include the ability to treat the entire ocular surface and the potential to
avoid the stem cell deficiency associated with extensive surgical excisions.10,11 Various topical agents have been advocated, including topical treatment with mitomycin C,12 5-fluorouracil,13 and interferon >-2b (IFN>2b).14,15 In this study, we have evaluated topical IFN>2b as a single therapy for primary OSSN and analyzed the outcomes and complications.
MATERIAL AND METHODS Medical records of patients with a diagnosis of primary OSSN who received topical IFN>2b between August 2012 and January 2014 at the Regional Institute of Ophthalmology were reviewed retrospectively. The diagnosis of OSSN was primarily clinical, based on thorough examination with slit-lamp biomicroscopy. Ocular surface squamous neoplasia were diagnosed with the characteristic appearance of highly vascularized, elevated, well-circumscribed growth and classified into papillomatous, gelatinous, and leukoplakic OSSN on the basis of macroscopic appearance. No incisional biopsy was performed due to the risk for malignant seeding potential. The demographic data with a history of risk factors were recorded. Patients with a history of any surgical or medical therapies before topical IFN>2b therapy were excluded. We recorded the clinical findings, including visual acuity and the diagnosis with all tumor characteristics. The staging was done according to the American Joint Committee on Cancer TNM staging system.16 Pretreatment and posttreatment tumor size was measured by the greatest linear diameter and limbal clock hours involvement. We used the standard dose of IFN>2b (1 million IU/mL), prepared by the reconstitution of 1 mL of recombinant IFN>2b injection (Zavinex 3 mIU/mL, zydus heptiza) with 2 mL of 0.9% sodium chloride and stored in refrigeration. The eye drops were administered 4 times daily until the complete clinical resolution of the tumor. Patients were monitored at monthly intervals by clinical examination until tumor regression, then every 3 months for 1 year and every 6 months thereafter. The response of the tumor (ie, size, vascularity, regression of lesion, or no change) to treatment was documented with clinical photographs at each visit. The total number of vials of topical IFN>2b and its related toxicity were recorded. Complete response was defined as the total disappearance of lesions with clear visibility of underlying structures. Recurrence was defined as the reappearance of a tumor at the same location or at any other location after complete resolution. No regression or change in tumor size after 3 months of topical therapy was labeled as failed treatment.
RESULTS From the *Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. Received for publication August 16, 2014; accepted November 26, 2014. The authors have no funding or conflicts of interest to declare. Reprints: Rakhi Kusumesh, MS, Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna, Bihar, India. Pin code 800014. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000104
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A total of 24 eyes of 24 patients with primary OSSN received topical IFN>2b. Twelve were male and 12 were female with the mean age of 62.44 T 13.65 years (range, 50Y92 years). The mean follow-up period was 18.81 T 3.81 months (range, 14Y22 months). The tumor characteristics including size and type are described in Table 1. Of the 24 tumors, 9 were papillomatous (Fig. 1A), 8 were gelatinous (Fig. 2), and 7 were leukoplakic (Fig. 3). Bulbar conjunctiva, cornea, and limbus
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TABLE 1. Tumor Characteristics Type of OSSN Tumor Papillomatous Gelatinous Leukoplakic Growth pattern Flat/sessile Pedunculated No. clock hours limbal involvement e3 4Y6 7Y9 10Y12 Tissue involved Bulbar conjunctiva Forniceal conjunctiva Tarsal conjunctiva Caruncle Cornea Mean greatest linear diameter, mm Risk factors HIV +ve HBsAg positive Smoking UV exposure
9 8 7 22 2 8 10 2 4 24 4 0 0 24 7.23 T 2.28 (median, 6 mm) 1 2 13 20
HIV +ve indicates human immunodeficiency virusYpositive; HBsAg, hepatitis B surface antigenYpositive; UV, ultraviolet.
FIGURE 2. Gelatinous OSSN involving cornea, bulbar, and palpebral conjunctiva.
were involved in all 24 patients. The median limbal involvement was 4 clock hours (mean, 5.58 clock hours; range, 2Y12 clock hours). Of 24 cases, 10 patients had 4 to 6 clock hours, and 4 had 360 degrees of limbal involvement. Twenty-one tumors were clinically staged as T3 (tumors invading adjacent structures excluding the orbit) and 3 as T2 (defined as the largest basal diameter 95 mm). Median greatest linear diameter was 6 mm (range, 5.2Y12 mm). Complete response was achieved in 22 tumors (91.6%). The median time to lesion resolution was 3.25 months in all successful remissions. Two (8.3%) of 24 patients failed to respond to topical IFN>2b; subsequently, they underwent surgical excision (Figs. 4, 5). Histopathological examination revealed SCC and a variant of SCC in the failed cases, respectively. Adverse effects of topical IFN>2b included spontaneous intratumoral bleeding after 3 weeks of topical therapy in 1 case (Fig. 1B). Consequently, the tumor shed off from its base (Figs. 1C, D). No long-term complication or recurrence was found at the end of the follow-up period. The duration of treatment, tumor response,
FIGURE 1. A, Papillomatous pedunculated OSSN. B, Spontaneous intratumoral bleeding after 3 weeks of topical therapy. C, Tumor shed off from its base after 2 weeks of bleeding. D, Complete resolution of tumor.
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FIGURE 3. Leukoplakic OSSN. FIGURE 5. Mucoepidermoid tumor.
adverse effects, and number of vials of topical IFN>2b are described in Table 2.
DISCUSSION Interferons are a family of glycoproteins that bind to cell surface receptors to promote antiviral and antitumor properties by activating immune cells, and they increase the recognition of tumor cells by up-regulating antigen presentation to T-lympocytes.17 Interferon >-2b is a recombinant form of interferon > that is approved by the US Food and Drug Administration for the treatment of several diseases. Some studies suggest that interferon may cause the inhibition of angiogenesis and human papillomavirus replication.18 The use of topical IFN>2b was reported first by Maskin19 in a multifocal limbal OSSN. Subsequently, Karp et al20 reported complete response in 5 cases of OSSN measuring less than 8 mm with IFN>2b. Topical therapy with IFN>2b, 1 million IU/mL, was evaluated in several series of primary and recurrent OSSN with 80% to 100% success.20Y23 We used the standard dose of topical IFN>2b (ie, 1 million IU/mL) and found complete response in 91.6% cases except 2 (8.3%) who failed to respond. Studies reported favorable results from using various concentrations and modes of IFN>2b for the treatment of primary and recurrent OSSN. Galor et al24,25 compared this dose with a 3 million IU/mL dose and found no comparative difference in tumor response, time to resolution, recurrence rate, or adverse effects. Although topical IFN>2b was effective for all types of OSSN including papillomatous, gelatinous, and leukoplakic, we found variable tumor responses among each type. In this study, we observed that gelatinous and papillomatous OSSN seemed to be more sensitive to therapy (not statistically proven). The greater sensitivity of the papilliform type was presumably due to the more rapidly dividing nature of the papilliform tumor as
FIGURE 4. Giant papillomatous OSSN with scleral adhesion. * 2015 Asia Pacific Academy of Ophthalmology
compared with the leukoplakic type, making it more susceptible to chemotherapy.26 The type and size of tumors may affect the duration of treatment as a result of variable clinical response. In our analysis, the median time to complete tumor resolution was 3.25 months (range, 2Y4 months). Several studies showed time to resolution of conjunctival intraepithelial neoplasia with IFN>2b ranging from 2 to 3 months.24,27 On the other hand, in a recent study by Shah et al,28 they found that the median time to complete tumor resolution was 6 months, which could be because most of the cases were advanced OSSN (classified as T3 according to the American Joint Committee on Cancer). In our study, although all patients had OSSN larger than 5.0 mm (mean, 7.23 T 2.28; range, 5.2Y12 mm) and adjacent tissue invasion such as cornea was present in all cases, we noted a shorter time for complete remission. We presume that this is because most of the tumors (70.8%) were gelatinous and papillomatous and hence more likely to resolve earlier. In addition, the corneal component of OSSN seemed to respond more rapidly than the bulbar conjunctival component, as observed previously by Karp et al.20 In the current study, no recurrence was seen at the end of follow-up. Two patients in this study failed to respond with topical IFN>2b. The first resistant case was a 90-year-old male patient who had a papillomatous sessile tumor larger than 12 mm with presence of scleral adhesion (Fig. 4). The second case of therapeutic failure was a 78-year-old male patient who had highly vascularized elevated growth with excessive mucous secretion over the lesion (Fig. 5). Both the first and second case underwent surgical excision and were histologically found to be SCC and a
TABLE 2. Treatment Information in Patients Treated With Topical Interferon for OSSN Successful Failed Time to lesion resolution, mo Time to follow-up, mo Average number of vials used until clinical resolution (range) Adverse effects Conjunctival congestion Intratumoral bleeding Foreign body sensation Tumor recurrence in eyes with successful topical therapy
22 (91.6%) 2 (8.3%) 3.25 (range, 2Y4) 18.81 T 3.8 3.41 T 0.48 (3Y4) 1 (4.2%) 2 (8.3%) 1 (4.2%) 0
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variant of SCC (ie, mucoepidermoid carcinoma). Treatment failure possibly occurred due to the large tumor size and presence of invasive SCC. In these tumors, longer duration or higher concentration of treatment might have been effective.24 Few adverse effects of topical IFN>2b have been reported, such as photophobia, follicular conjunctivitis, and conjunctival hyperemia.20 In the present study, conjunctival hyperemia with foreign body sensation was present in 1 patient (4.2%). One patient (4.2%) developed spontaneous intratumoral bleeding after 3 weeks of topical IFN>2b in a pedunculated papillomatous tumor. Perhaps regression of the tumor size resulted in increased mobility of the tumor, leading to mechanical trauma and bleeding. Another possible cause of intratumoral bleeding could be the use of topical IFN>2b. To the best of our knowledge, the occurrence of spontaneous intratumoral bleeding has never been reported in the literature. None of the 24 patients treated with topical IFN>2b in our study discontinued therapy due to adverse effects. According to a review by Poothullil and Colby,29 the rates of CIN regression with 3 topical agents (ie, mitomycin C, 5fluorouracil, and IFN>2b) are comparable (80%Y88%). Conversely, topical IFN>2b has no ocular surface toxicity or known carcinogenic potential as does topical mitomycin C.30Y32 In conclusion, considering the difficulty of complete eradication and potential surgical complications associated with treating OSSN, we believe that topical IFN>2b is effective as a single therapy in the management of primary OSSN with minimal selflimited adverse effects. It may provide the least invasive way of treating OSSN, and it appears to be a safe alternative to radiation, topical mitomycin C, intralesional IFN>2b injection, and surgical excision with cryotherapy. REFERENCES 1. Lee GA, Williams G, Hirst LW, et al. Risk factors in the development of ocular surface epithelial dysplasia. Ophthalmology. 1994;101:360Y364. 2. Napora C, Cohen EJ, Genvert GI, et al. Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg. 1990;21:27Y30. 3. McDonnell JM, McDonnell PJ, Sun YY. Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia. Invest Ophthalmol Vis Sci. 1992;33:184Y189. 4. Karp CL, Scott IU, Chang TS, et al. Conjunctival intraepithelial neoplasia: a possible marker for human immunodeficiency virus infection? Arch Ophthalmol. 1996;114:257Y261. 5. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995;39:429Y450. 6. Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctival tumors and squamous cell carcinomas. Am J Ophthalmol. 1983;95:359Y363.
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12. Rozenman Y, Frucht-Pery J. Treatment of conjunctival intraepithelial neoplasia with topical drops of mitomycin C. Cornea. 2000;19:1Y6. 13. Midena E, Angeli CD, Valenti M, et al. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84:268Y272. 14. Boehm MD, Huang AJ. Treatment of recurrent corneal and conjunctival intraepithelial neoplasia with topical interferon alfa 2b. Ophthalmology. 2004;111:1755Y1761. 15. Holcombe DJ, Lee GA. Topical interferon alfa-2b for the treatment of recalcitrant ocular surface squamous neoplasia. Am J Ophthalmol. 2006;142:568Y571. 16. Edge SB, Byrd DR, Crompton CC et al, eds. Carcinoma of conjunctiva. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:531Y537. 17. Baron S, Tyring SK, Fleischmann WR Jr, et al. The interferons: mechanisms of action and clinical applications. JAMA. 1991;266:1375Y1383. 18. Majewski S, Szmurlo A, Marczak M, et al. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines. Int J Cancer. 1994;57:81Y85. 19. Maskin SL. Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol. 1994;112:1145Y1146. 20. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology. 2001;108:1093Y1098. 21. Schechter BA, Schrier A, Nagler RS, et al. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea. 2002;21:6Y11. 22. Sturges A, Butt AL, Lai JE, et al. Topical interferon or surgical excision for the management of primary ocular surface squamous neoplasia. Ophthalmology. 2008;115:1297Y1302. 23. 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;32:248Y256. 24. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol. 2010;94:551Y554. 25. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119:1974Y1981. 26. Wilson MW, Hungerford JL, George SM, et al. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol. 1997;124:303Y311. 27. Schechter BA, Koreishi AF, Karp CL, et al. Long-term follow-up of conjunctival and corneal intraepithelial neoplasia treated with topical interferon alfa-2b. Ophthalmology. 2008;115:1291Y1296.
7. Peksayar G, Soytu¨rk MK, Demiryont M. Long-term results of cryotherapy on malignant epithelial tumors of the conjunctiva. Am J Ophthalmol. 1989;107:337Y349.
28. Shah SU, Kaliki S, Kim HJ. Topical interferon alfa-2b for management of ocular surface squamous neoplasia in 23 cases. Outcomes based on American Joint Committee on Cancer classification. Arch Ophthalmol. 2012;130:159Y164.
8. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology. 2007;114:976Y982.
29. Poothullil AM, Colby KA. Topical medical therapies for ocular surface tumors. Semin Ophthalmol. 2006;21:161Y169.
9. Besley J, Pappalardo J, Lee GA, et al. Risk factors for ocular surface squamous neoplasia recurrence after treatment with topical mitomycin C and interferon alpha-2b. Am J Ophthalmol. 2014;157:287Y293. 10. Sepulveda R, Pe’er J, Midena E, et al. Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol. 2010;94:532Y535. 11. Kim JW, Abramson DH. Topical treatment options for conjunctival neoplasms. Clin Ophthalmol. 2008;2:503Y515.
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30. Cartsburg O, Kallen C, Hillenkamp J, et al. Topical mitomycin C and radiation induce conjunctival DNA-polyploidy. Anal Cell Pathol. 2001;23:65Y74. 31. Dogru M, Erturk H, Shimazaki J, et al. Tear function and ocular surface changes with topical mitomycin (MMC) treatment for primary corneal intraepithelial neoplasia. Cornea. 2003;22:627Y639. 32. Dudney BW, Malecha MA. Limbal stem cell deficiency following topical mitomycin C treatment of conjunctival-corneal intraepithelial neoplasia. Am J Ophthalmol. 2004;137:950Y951.
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Topical Interferon >-2b as a Single Therapy for Primary Ocular Surface Squamous Neoplasia Rakhi Kusumesh, MS,* Anita Ambastha, MS,* Bibhuti Sinha, MS,* and Rajiv Kumar, MD*
Purpose: The aim of this study was to evaluate the efficacy and safety of topical interferon >-2b (IFN>2b) as a single therapy for primary ocular surface squamous neoplasia (OSSN). Methods: Medical records of 24 eyes of 24 patients with primary OSSN were reviewed retrospectively. The diagnosis of OSSN was primarily based on the slit-lamp examination. All cases were treated with topical IFN>2b (1 million IU/mL) 4 times daily. The duration of treatment, tumor response, adverse effects, and number of vials of topical IFN>2b were noted. Complete response was defined as total disappearance of lesions. Results: The complete remission of the tumor was observed in 22 patients (91.6%). Two patients (8.3%) did not respond to the treatment. The mean age was 62.44 T 13.65 years (range, 50Y92 years). The mean follow-up period was 18.81 T 3.81 months (range, 14Y22 months). The median greatest linear dimension was 6 mm (range, 5.2Y12 mm). In all successful remissions, the median time to lesion resolution was 3.25 months. Adverse effects of topical IFN>2b included spontaneous intratumoral bleeding after 3 weeks of topical therapy in 1 patient. No long-term complication or recurrence was found at the end of the follow-up period. Conclusions: Topical IFN>2b is effective and safe as a single therapy in the management of primary OSSN with minimal self-limited adverse effects. It may provide the least invasive way of treating OSSN. Key Words: tumor, OSSN, topical, interferon >-2b, intratumoral bleeding (Asia Pac J Ophthalmol 2015;4: 279Y282)
O
cular surface squamous neoplasia (OSSN) is a spectrum of malignancy that includes intraepithelial dysplasia, carcinoma in situ (CIN) of the conjunctiva and cornea, and invasive squamous cell carcinoma (SCC). Risk factors for this disease are ultraviolet light exposure, petroleum products, heavy cigarette smoking, human papillomavirus infection, and human immunodeficiency virus infection.1Y5 Surgical excision with adjunctive cryotherapy was previously considered the treatment of choice for OSSN.5Y7 However, evidence suggests that microscopic signs of OSSN extend far beyond the macroscopic edges of the tumors, resulting in a relatively high risk of OSSN recurrence after surgery.8,9 Medical treatment alone or as an adjuvant has been used increasingly for these tumors. Possible advantages of medical therapy include the ability to treat the entire ocular surface and the potential to
avoid the stem cell deficiency associated with extensive surgical excisions.10,11 Various topical agents have been advocated, including topical treatment with mitomycin C,12 5-fluorouracil,13 and interferon >-2b (IFN>2b).14,15 In this study, we have evaluated topical IFN>2b as a single therapy for primary OSSN and analyzed the outcomes and complications.
MATERIAL AND METHODS Medical records of patients with a diagnosis of primary OSSN who received topical IFN>2b between August 2012 and January 2014 at the Regional Institute of Ophthalmology were reviewed retrospectively. The diagnosis of OSSN was primarily clinical, based on thorough examination with slit-lamp biomicroscopy. Ocular surface squamous neoplasia were diagnosed with the characteristic appearance of highly vascularized, elevated, well-circumscribed growth and classified into papillomatous, gelatinous, and leukoplakic OSSN on the basis of macroscopic appearance. No incisional biopsy was performed due to the risk for malignant seeding potential. The demographic data with a history of risk factors were recorded. Patients with a history of any surgical or medical therapies before topical IFN>2b therapy were excluded. We recorded the clinical findings, including visual acuity and the diagnosis with all tumor characteristics. The staging was done according to the American Joint Committee on Cancer TNM staging system.16 Pretreatment and posttreatment tumor size was measured by the greatest linear diameter and limbal clock hours involvement. We used the standard dose of IFN>2b (1 million IU/mL), prepared by the reconstitution of 1 mL of recombinant IFN>2b injection (Zavinex 3 mIU/mL, zydus heptiza) with 2 mL of 0.9% sodium chloride and stored in refrigeration. The eye drops were administered 4 times daily until the complete clinical resolution of the tumor. Patients were monitored at monthly intervals by clinical examination until tumor regression, then every 3 months for 1 year and every 6 months thereafter. The response of the tumor (ie, size, vascularity, regression of lesion, or no change) to treatment was documented with clinical photographs at each visit. The total number of vials of topical IFN>2b and its related toxicity were recorded. Complete response was defined as the total disappearance of lesions with clear visibility of underlying structures. Recurrence was defined as the reappearance of a tumor at the same location or at any other location after complete resolution. No regression or change in tumor size after 3 months of topical therapy was labeled as failed treatment.
RESULTS From the *Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India. Received for publication August 16, 2014; accepted November 26, 2014. The authors have no funding or conflicts of interest to declare. Reprints: Rakhi Kusumesh, MS, Regional Institute of Ophthalmology, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna, Bihar, India. Pin code 800014. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000104
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A total of 24 eyes of 24 patients with primary OSSN received topical IFN>2b. Twelve were male and 12 were female with the mean age of 62.44 T 13.65 years (range, 50Y92 years). The mean follow-up period was 18.81 T 3.81 months (range, 14Y22 months). The tumor characteristics including size and type are described in Table 1. Of the 24 tumors, 9 were papillomatous (Fig. 1A), 8 were gelatinous (Fig. 2), and 7 were leukoplakic (Fig. 3). Bulbar conjunctiva, cornea, and limbus
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TABLE 1. Tumor Characteristics Type of OSSN Tumor Papillomatous Gelatinous Leukoplakic Growth pattern Flat/sessile Pedunculated No. clock hours limbal involvement e3 4Y6 7Y9 10Y12 Tissue involved Bulbar conjunctiva Forniceal conjunctiva Tarsal conjunctiva Caruncle Cornea Mean greatest linear diameter, mm Risk factors HIV +ve HBsAg positive Smoking UV exposure
9 8 7 22 2 8 10 2 4 24 4 0 0 24 7.23 T 2.28 (median, 6 mm) 1 2 13 20
HIV +ve indicates human immunodeficiency virusYpositive; HBsAg, hepatitis B surface antigenYpositive; UV, ultraviolet.
FIGURE 2. Gelatinous OSSN involving cornea, bulbar, and palpebral conjunctiva.
were involved in all 24 patients. The median limbal involvement was 4 clock hours (mean, 5.58 clock hours; range, 2Y12 clock hours). Of 24 cases, 10 patients had 4 to 6 clock hours, and 4 had 360 degrees of limbal involvement. Twenty-one tumors were clinically staged as T3 (tumors invading adjacent structures excluding the orbit) and 3 as T2 (defined as the largest basal diameter 95 mm). Median greatest linear diameter was 6 mm (range, 5.2Y12 mm). Complete response was achieved in 22 tumors (91.6%). The median time to lesion resolution was 3.25 months in all successful remissions. Two (8.3%) of 24 patients failed to respond to topical IFN>2b; subsequently, they underwent surgical excision (Figs. 4, 5). Histopathological examination revealed SCC and a variant of SCC in the failed cases, respectively. Adverse effects of topical IFN>2b included spontaneous intratumoral bleeding after 3 weeks of topical therapy in 1 case (Fig. 1B). Consequently, the tumor shed off from its base (Figs. 1C, D). No long-term complication or recurrence was found at the end of the follow-up period. The duration of treatment, tumor response,
FIGURE 1. A, Papillomatous pedunculated OSSN. B, Spontaneous intratumoral bleeding after 3 weeks of topical therapy. C, Tumor shed off from its base after 2 weeks of bleeding. D, Complete resolution of tumor.
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Topical Interferon >-2b for Primary OSSN
FIGURE 3. Leukoplakic OSSN. FIGURE 5. Mucoepidermoid tumor.
adverse effects, and number of vials of topical IFN>2b are described in Table 2.
DISCUSSION Interferons are a family of glycoproteins that bind to cell surface receptors to promote antiviral and antitumor properties by activating immune cells, and they increase the recognition of tumor cells by up-regulating antigen presentation to T-lympocytes.17 Interferon >-2b is a recombinant form of interferon > that is approved by the US Food and Drug Administration for the treatment of several diseases. Some studies suggest that interferon may cause the inhibition of angiogenesis and human papillomavirus replication.18 The use of topical IFN>2b was reported first by Maskin19 in a multifocal limbal OSSN. Subsequently, Karp et al20 reported complete response in 5 cases of OSSN measuring less than 8 mm with IFN>2b. Topical therapy with IFN>2b, 1 million IU/mL, was evaluated in several series of primary and recurrent OSSN with 80% to 100% success.20Y23 We used the standard dose of topical IFN>2b (ie, 1 million IU/mL) and found complete response in 91.6% cases except 2 (8.3%) who failed to respond. Studies reported favorable results from using various concentrations and modes of IFN>2b for the treatment of primary and recurrent OSSN. Galor et al24,25 compared this dose with a 3 million IU/mL dose and found no comparative difference in tumor response, time to resolution, recurrence rate, or adverse effects. Although topical IFN>2b was effective for all types of OSSN including papillomatous, gelatinous, and leukoplakic, we found variable tumor responses among each type. In this study, we observed that gelatinous and papillomatous OSSN seemed to be more sensitive to therapy (not statistically proven). The greater sensitivity of the papilliform type was presumably due to the more rapidly dividing nature of the papilliform tumor as
FIGURE 4. Giant papillomatous OSSN with scleral adhesion. * 2015 Asia Pacific Academy of Ophthalmology
compared with the leukoplakic type, making it more susceptible to chemotherapy.26 The type and size of tumors may affect the duration of treatment as a result of variable clinical response. In our analysis, the median time to complete tumor resolution was 3.25 months (range, 2Y4 months). Several studies showed time to resolution of conjunctival intraepithelial neoplasia with IFN>2b ranging from 2 to 3 months.24,27 On the other hand, in a recent study by Shah et al,28 they found that the median time to complete tumor resolution was 6 months, which could be because most of the cases were advanced OSSN (classified as T3 according to the American Joint Committee on Cancer). In our study, although all patients had OSSN larger than 5.0 mm (mean, 7.23 T 2.28; range, 5.2Y12 mm) and adjacent tissue invasion such as cornea was present in all cases, we noted a shorter time for complete remission. We presume that this is because most of the tumors (70.8%) were gelatinous and papillomatous and hence more likely to resolve earlier. In addition, the corneal component of OSSN seemed to respond more rapidly than the bulbar conjunctival component, as observed previously by Karp et al.20 In the current study, no recurrence was seen at the end of follow-up. Two patients in this study failed to respond with topical IFN>2b. The first resistant case was a 90-year-old male patient who had a papillomatous sessile tumor larger than 12 mm with presence of scleral adhesion (Fig. 4). The second case of therapeutic failure was a 78-year-old male patient who had highly vascularized elevated growth with excessive mucous secretion over the lesion (Fig. 5). Both the first and second case underwent surgical excision and were histologically found to be SCC and a
TABLE 2. Treatment Information in Patients Treated With Topical Interferon for OSSN Successful Failed Time to lesion resolution, mo Time to follow-up, mo Average number of vials used until clinical resolution (range) Adverse effects Conjunctival congestion Intratumoral bleeding Foreign body sensation Tumor recurrence in eyes with successful topical therapy
22 (91.6%) 2 (8.3%) 3.25 (range, 2Y4) 18.81 T 3.8 3.41 T 0.48 (3Y4) 1 (4.2%) 2 (8.3%) 1 (4.2%) 0
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variant of SCC (ie, mucoepidermoid carcinoma). Treatment failure possibly occurred due to the large tumor size and presence of invasive SCC. In these tumors, longer duration or higher concentration of treatment might have been effective.24 Few adverse effects of topical IFN>2b have been reported, such as photophobia, follicular conjunctivitis, and conjunctival hyperemia.20 In the present study, conjunctival hyperemia with foreign body sensation was present in 1 patient (4.2%). One patient (4.2%) developed spontaneous intratumoral bleeding after 3 weeks of topical IFN>2b in a pedunculated papillomatous tumor. Perhaps regression of the tumor size resulted in increased mobility of the tumor, leading to mechanical trauma and bleeding. Another possible cause of intratumoral bleeding could be the use of topical IFN>2b. To the best of our knowledge, the occurrence of spontaneous intratumoral bleeding has never been reported in the literature. None of the 24 patients treated with topical IFN>2b in our study discontinued therapy due to adverse effects. According to a review by Poothullil and Colby,29 the rates of CIN regression with 3 topical agents (ie, mitomycin C, 5fluorouracil, and IFN>2b) are comparable (80%Y88%). Conversely, topical IFN>2b has no ocular surface toxicity or known carcinogenic potential as does topical mitomycin C.30Y32 In conclusion, considering the difficulty of complete eradication and potential surgical complications associated with treating OSSN, we believe that topical IFN>2b is effective as a single therapy in the management of primary OSSN with minimal selflimited adverse effects. It may provide the least invasive way of treating OSSN, and it appears to be a safe alternative to radiation, topical mitomycin C, intralesional IFN>2b injection, and surgical excision with cryotherapy. REFERENCES 1. Lee GA, Williams G, Hirst LW, et al. Risk factors in the development of ocular surface epithelial dysplasia. Ophthalmology. 1994;101:360Y364. 2. Napora C, Cohen EJ, Genvert GI, et al. Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg. 1990;21:27Y30. 3. McDonnell JM, McDonnell PJ, Sun YY. Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia. Invest Ophthalmol Vis Sci. 1992;33:184Y189. 4. Karp CL, Scott IU, Chang TS, et al. Conjunctival intraepithelial neoplasia: a possible marker for human immunodeficiency virus infection? Arch Ophthalmol. 1996;114:257Y261. 5. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol. 1995;39:429Y450. 6. Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctival tumors and squamous cell carcinomas. Am J Ophthalmol. 1983;95:359Y363.
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12. Rozenman Y, Frucht-Pery J. Treatment of conjunctival intraepithelial neoplasia with topical drops of mitomycin C. Cornea. 2000;19:1Y6. 13. Midena E, Angeli CD, Valenti M, et al. Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. Br J Ophthalmol. 2000;84:268Y272. 14. Boehm MD, Huang AJ. Treatment of recurrent corneal and conjunctival intraepithelial neoplasia with topical interferon alfa 2b. Ophthalmology. 2004;111:1755Y1761. 15. Holcombe DJ, Lee GA. Topical interferon alfa-2b for the treatment of recalcitrant ocular surface squamous neoplasia. Am J Ophthalmol. 2006;142:568Y571. 16. Edge SB, Byrd DR, Crompton CC et al, eds. Carcinoma of conjunctiva. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:531Y537. 17. Baron S, Tyring SK, Fleischmann WR Jr, et al. The interferons: mechanisms of action and clinical applications. JAMA. 1991;266:1375Y1383. 18. Majewski S, Szmurlo A, Marczak M, et al. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines. Int J Cancer. 1994;57:81Y85. 19. Maskin SL. Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol. 1994;112:1145Y1146. 20. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology. 2001;108:1093Y1098. 21. Schechter BA, Schrier A, Nagler RS, et al. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea. 2002;21:6Y11. 22. Sturges A, Butt AL, Lai JE, et al. Topical interferon or surgical excision for the management of primary ocular surface squamous neoplasia. Ophthalmology. 2008;115:1297Y1302. 23. 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;32:248Y256. 24. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neoplasia: a dose comparison study. Br J Ophthalmol. 2010;94:551Y554. 25. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119:1974Y1981. 26. Wilson MW, Hungerford JL, George SM, et al. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol. 1997;124:303Y311. 27. Schechter BA, Koreishi AF, Karp CL, et al. Long-term follow-up of conjunctival and corneal intraepithelial neoplasia treated with topical interferon alfa-2b. Ophthalmology. 2008;115:1291Y1296.
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30. Cartsburg O, Kallen C, Hillenkamp J, et al. Topical mitomycin C and radiation induce conjunctival DNA-polyploidy. Anal Cell Pathol. 2001;23:65Y74. 31. Dogru M, Erturk H, Shimazaki J, et al. Tear function and ocular surface changes with topical mitomycin (MMC) treatment for primary corneal intraepithelial neoplasia. Cornea. 2003;22:627Y639. 32. Dudney BW, Malecha MA. Limbal stem cell deficiency following topical mitomycin C treatment of conjunctival-corneal intraepithelial neoplasia. Am J Ophthalmol. 2004;137:950Y951.
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