Long term use of topical interpheron alpha 2-b for recurrent conjunctival squamous neoplasia

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1 CASE REPORT Long term use of topical interpheron alpha 2-b for recurrent conjunctival squamous neoplasia Luis Fernández-Vega Cueto, MD 1,2 ; Paula Verdaguer, MD 1.3 ; Juan Alvarez de Toledo, MD 1,3 ; M. Fideliz de la Paz, MD 1,3 CASE STUDY: An 80-year-old woman diagnosed with a recurring conjunctival squamous cell carcinoma treated by surgical excision of the lesion, ocular surface reconstruction and topical interferon alpha 2-b. DISCUSSION: Squamous cell carcinoma is the most frequent malignant tumour of the ocular surface. Surgical removal of the lesion is the traditional treatment for these tumours, but this technique has a high recurrence rate. Immunotherapy is the current alternative for these carcinomas. Recent studies have proven the effectivity of interferon against epithelial neoplasms of the ocular surface. We could consider life-long treatments with topic interferon depending on the clinical characteristics of the patient, as its side effects are uncommon. KEYWORDS: Squamous neoplasia, interferon. J Emmetropia 2012; 3: INTRODUCTION Submitted: 1/3/12 Revised: 5/30/12 Accepted: 6/4/12 This case report is a follow up of the previously published in Arch Soc Esp Oftalmol, 86: 5; and titled «Interferón alfa 2-beta, queratectomía parcial y trasplante de membrana amniótica para el tratamiento de un carcinoma escamoso conjuntival recidivante». 1 Centro de Oftalmología Barraquer. 2 Residente de Oftalmología. 3 Adjunto de Oftalmología. Every neoplastic lesion of epithelial origin in the cornea and in the conjunctiva is known as Ocular Surface Squamous Neoplasia (OSSN) and includes squamous dysplasia, carcinoma in situ (CIS) and invasive squamous cell carcinoma 1,2. Squamous dysplasia is characterised by presenting only one part of the epithelial thickness substituted by anomalous cells, while carcinoma in situ is a neoplasm with severe dysplasia of the whole epithelial thickness, the basement membrane remains intact in both cases. Dysplasias can progress to carcinoma in situ, and even though they are generally indolent lesions, they are the precursor of invasive squamous cell carcinoma in which the anomalous cells spread beyond the basement membrane 3,4. The aggressive surgical treatment with wide safety margins described by Shields et al 5 seems to be the most efficient way to avoid the high rate of recurrences previously described with surgical excision related to co-adjuvant cryotherapy 6. However, because of the relatively high risk of recurrences after surgery due to the difficulties of obtaining edges that are not infiltrated, the use of topic treatments such as mitomycin C 7,8, 5-fluorouracil 9 and interferon alpha 2-b as only therapy is gaining wider acceptance 1, CASE REPORT An 80-year-old woman was referred to us by another department due to a conjuctival tumour in the right eye (RE) 5 months prior. Personal history of interest included the removal of a small upper-external palpebral papilloma in the RE one year ago. Corrected visual acuity (VA) in RE, measured with Snellen optotypes, was of 0.65 and in the left eye (LE) of 0.8. The ophthalmological exploration carried out in the RE revealed a conjunctival lesion with the appearance of a papilloma in the internal edge, involving the halfmoon fold and caruncle with dilated capillary crests and extension to the sclera-corneal limbus at approximately 3 o clock. The lesion was more prominent in the lower area, slightly displacing the lower eyelid and causing a discrete ectropion of the middle third of the palpebral edge. The new tissue comprised the inferior and superior lachrymal puncta and was extended toward the skin of the internal edge. An ulcerated cutaneous lesion was also observed in the upper eyelid with chronic inflammatory signs (fig. 1). The patient provided the anatomo-pathological report of the lesion biopsy that revealed squamous cell SECOIR Sociedad Española de Cirugía Ocular Implanto-Refractiva ISSN:

2 INTERPHERON ALPHA-2b FOR RECURRENT COJUNCTIVAL SQUAMOUS NEOPLASIA 91 Figure 1. Papillomatous tumouration of the nasal bulbar conjunctiva that invades the half-moon fold, the caruncle, the internal edge, the superior and inferior lacrimal points, the superior palpebral edge where it causes skin ulceration, and the inferior palpebral edge. carcinoma. Nuclear magnetic resonance was performed to discard retro-ocular infiltration. Considering the diagnostic orientation of squamous carcinoma involving the superior and inferior eyelids and the nasal conjunctiva of the right eye, the patient underwent surgery to remove the lesion and to reconstruct the affected area using a free conjunctival graft obtained from the temporal quadrant placed over the middle rectus area and a muscle-skin pediculated graft to repair the internal edge. Biopsies were made on all the removed fragments, a follow-up by a general oncologist was recommended. The initial surgical and functional result was excellent and the anatomo-pathological report of the lesion confirmed the diagnosis of squamous carcinoma with resection margins free of lesion at the palpebral level and infiltrating squamous carcinoma with a minimum damaged area which makes contact with the resection edge in the bulbar conjunctiva of the sclerocorneal limbus. Due to said location, we decided to closely observe the clinical evolution of the case. Fourteen months after the intervention, in a regular check-up a white-greyish lesion was observed with vascularisation and corneal infiltration between 12 and 6.30 o clock in the nasal quadrant. A 3.8 mm geograph- Figure 2. Appearance after the first intervention. Good palpebral reconstruction. Vascularised half-moon lesion with clinical neoplasia recurrence signs and geographic epithelial defect in the nasal paracentral sector.

3 92 INTERPHERON ALPHA-2b FOR RECURRENT COJUNCTIVAL SQUAMOUS NEOPLASIA Figure 3. Appearance of the cornealconjunctival lesion after the first 4-month application of interferon eye drops. The appearance of the lesion in the conjunctival area has not worsened even though growth is observed, with increased neovascularisation in the corneal area. ic corneal epithelial defect was seen, with thinning at 3 o clock close to the limbus (fig. 2). A diagnosis of recurring conjunctival carcinoma was suspected, treatment with interferon alpha 2-b in a concentration of UI/ml 5 times a day during 2 months was initiated. In this period an initial reduction of the epithelial defect and a regression of the recurrence was observed. Given the favorable evolution, we decided to continue the topical treatment, but 4 months later an extension of the lesion was observed over the cornea (fig. 3). Due to the diagnostic impression of relapsing squamous carcinoma, the recurring lesion was surgically removed with a partial lamellar half-moon keratectomy performed with 2 trephines of different diameters, resection of the entire nasal bulbar conjunctiva and reconstruction of all the resected area with an amniotic membrane graft. This membrane was fixed with a continuous 10-0 nylon suture using transfixating points and anchoring it to the superficial scleral layers to avoid early dislocation (fig. 4). Five days after the intervention and after removing the occlusive bandage, topical treatment was resumed with interferon alpha 2-b 5 times a day. In the immediate postoperative period, the amniotic membrane remained in position until it was completely reabsorbed without dislocation; this was attributed to the continuous suture with numerous anchoring points. Once verified the complete disappearance of the membrane, the suture was withdrawn. The nasal bulbar conjunctiva epithelialized adequately and no signs of carcinoma recurrence were observed during the followup period. Conjunctival impression cytologies were performed to monitor the histological appearance of Figure 4. Result one month after the second intervention. The amniotic membrane remains in position. There is no epithelial defect in the cornea or the conjunctiva.

4 INTERPHERON ALPHA-2b FOR RECURRENT COJUNCTIVAL SQUAMOUS NEOPLASIA 93 Figure 5. In spite of the pain there were no signs of tumour recurrence. Only a symblepharon is observed in the nasal area. The impression cytology was negative too. the corneal epithelial and superficial conjunctival cells due to the degree of invasion of the area caused by the lesion in its initial stages, even though its systematic execution is being called into question. After a 15-month follow-up and the second surgery no visible recurrence was observed, with a corrected VA of 0.65 in the right eye. The patient received interferon alpha 2-b eye drops 5 times a day and artificial tears, but she came back to our centre 6 months after the last visit, reporting pain in the RE and with the recommendation of her oncologist to undergo another eye check. A symblepharon in the nasal area without signs of tumour recurrence was evidenced in the ophthalmologic examination (fig. 5). A conjuctival impression cytology of the affected area was performed; a diagnostic of loss of goblet cells without keratinisation was obtained. After 6 months without signs of tumour recurrence, the topical treatment with interferon alpha 2-b was discontinued. However, in her follow-up visit 6 months later, she came to our centre reporting pain and a loss of VA in the RE. A corrected VA of 0.35 was observed in the RE and in the ophthalmologic examination showed a marked hyperaemia in the nasal area with symblepharon, neovascularisation in the inferior nasal quadrant of the cornea and an epithelial defect of 0,2 mm (fig. 6). It was then decided that the treatment with interferon alpha 2-b 5 times a day was to be reinstilled again. 15 days later the epithelial defect was completely closed and there was practically no conjunctival hyperaemia. After a 6 months follow-up there was no visible recurrence with a corrected VA of 0.55 in the RE. Currently, the patient remains under treatment with interferon alpha 2-b eye Figure 6. Appearance at the last alleged recurrence. High hyperaemia in the nasal area with symblepharon, neovascularisation in the inferior nasal quadrant and an epithelial defect of 0,2 mm in the cornea.

5 94 INTERPHERON ALPHA-2b FOR RECURRENT COJUNCTIVAL SQUAMOUS NEOPLASIA drops 5 times a day with no evidence of new lesions or side effects due to the medication. DISCUSSION Conjunctival squamous neoplasia is the most frequent malignant tumour of the ocular surface. Initially, this lesion is confined inside the epithelium strata and is known as conjunctival intraepithelial neoplasia (CIN). There are 3 stages of CIN depending on if the lesion affects: the external third (stage I CIN or mild dysplasia), the two external thirds (stage II CIN or moderate dysplasia) or the thickness of the entire epithelium (stage III CIN or severe dysplasia or in situ carcinoma). It appears as a slowly progressing unilateral lesion with a low malignant potential 13. Predominantly, it is found in elderly males. When the neoplastic cell growth goes through the basement membrane it is known as invasive squamous carcinoma. Its aetiology is not entirely clear and it could possibly be due to multiple factors. It could represent an abnormal maturation of the corneal and conjunctival epithelium as the combination of factors such as: ultraviolet B radiation and human papilloma virus 16 and 18 14, cigarette smoke, chemical products or HIV 15. Clinically speaking, these lesions are low in height, of variable shape and clearly differentiated from surrounding normal tissue. They are usually accompanied by nutritional vascularization and its colour ranges from pearl grey to greyish red. They are usually located at the nasal limbus, possibly due to the greater exposure to UV radiation of the nasal area or, less frequently, in the temporal conjunctival area in the interpalpebral fissure. It is necessary to perform a histological diagnosis before beginning the treatment, always depending on the size of the lesion. In small lesions, a complete excisional biopsy of the same is the most frequently used technique. In large or extensive tumours, small focal biopsies can be carried out to determine the diagnostic and plan the most adequate surgical technique. A recent alternative consists of obtaining cytological samples either through impression or brushing for the diagnostic and postoperative monitoring period. The traditional method for treating these tumours is a simple surgery, a simple resection of the lesion even though it exhibits a high recurrence rate (25-53%) due to the difficulty in obtaining edges without infiltration. If the underlying corneal or scleral tissue is invaded, it could be necessary to perform lamellar keratoplasty and scleroplasty. When carrying out broad resections, it is necessary to use tissue to rebuild the surgical resection surface. We can use rotational pediculated conjunctival flaps, free conjunctival flaps from the same eye or from the other one or, in cases of large resections it would be advisable to use amniotic membrane, as in this particular case. It is important to use a polished suture technique if we use amniotic membrane to cover the treated area, as the tendency toward dislocation observed with this tissue is significant. Our preference is for a continuous suture technique anchored in the sclera following the entire anterior, lateral and posterior edges of the implanted membrane. The size of the membrane is adjusted to the area in which the resection has been performed. Likewise, it is extremely important to use a meticulous surgical technique following the non-touch technique proposed by Shields 5 to avoid the dispersion of tumour cells during surgery and the subsequence local recurrences. With this technique, the lesion must be resected starting from healthy tissue about 4 mm beyond the discernible edges of the lesion. The aforementioned must not be touched or washed with any saline solution to avoid the dissemination of neoplastic cells that could take hold and prompt a recurrence. Bleeding scleral and conjunctival vessels must be carefully cauterised, a fine layer of sclera at the base of the lesion must be withdrawn. In addition, absolute alcohol must be applied with a sponge to induce necrosis and eliminate cells from the entire resection substrate. A two-step cryocoagulation of all the conjunctival margins of the resection must be carried out afterwards. Radiotherapy (strontium-90, b-therapy, and g-therapy) is no longer used due to its frequent and dangerous complications, but it may be necessary in large lesions and always in association with other procedures. Topical chemotherapy has been proposed for treating primary conjunctival tumours and after recurrences, although the limited penetration of these agents can cause failures in the eradication of the tumour. The most widely used drugs are 5-fluorouracil 9 and mitomycin C 7,8. Immunotherapy can be used as an alternative or as a supplementary therapy for treating these lesions. Interferons are glycoproteins that activate a cascade of intracellular events that confer antiviral and antitumor properties. Interferon alpha 2-b can be applied topically as eye drops or through an injection in the lesion. Its administration has been described as the initial and isolated treatment for conjunctival intraepithelial neoplasias and as supplementary therapy to surgery of invasive squamous carcinomas, providing good results with low side effect rates 16,17. Boehm described topical interferon treatment in a series of 7 eyes with recurrenced conjunctival and corneal intraepithelial neoplasia in a frequency of 4 times a day up to resolution, with a mean time up to elimination of the tumour of 14.5 weeks 18. The side effects of the topical application of interferon are usually mild and consist of conjunctival hyper-

6 INTERPHERON ALPHA-2b FOR RECURRENT COJUNCTIVAL SQUAMOUS NEOPLASIA 95 aemia and follicular conjunctivitis, which were not observed in our patient. According to our experience, mitomycin C has more serious side effects on the ocular surface such as scleral melting or epithelial defects and their use would be more limited in time. In this clinical case, the utilization of interferon alpha 2-b after the first recurrence showed temporary efficacy because even though in the first 2 months the lesion reduced its size and the corneal epithelial defect epithelised, subsequently it increased in size. In the second recurrence, immediately after surgery treatment was initiated with interferon alpha 2-b and, after 30 months follow-up we have not observed a recurrence of the conjunctival carcinoma as described by some authors 19. This is why the treatment with interferon alpha 2-b is discontinued at this moment. However, 6 months later it is started again as a potential recurrence is suspected, the patient perceives improvement a few days later. In this case, considering the evolution and aggressiveness of the initial lesion and the absence of observed local side effects, it was decided to continue the long-term administration of the interferon eye drops. The last suspicion of recurrence when the treatment was discontinued and the immediate improvement after it was continued makes us consider the possibility of maintaining life-long treatment with topical interferon alpha 2-b in some cases, as long as there are no side effects for the patient. REFERENCES 1. Sturges A, Butt A, Lai J, Chodosh J. Topical interferon or surgical excision for the management of primary ocular surface squamous neoplasia. Ophtalmology 2008; 115: Lee G, Hirst L. Ocular surface squamous neoplasia. Surv Ophtalmol 1995; 39: Quintana R, Folch J. Tratamiento farmacológico de las neoplasias intraepiteliales de la córnea y conjuntiva. Annals d Oftalmología 2002; 10: Saornil M, Becerra E, Méndez M, Blanco G. Conjunctival tumors. Arch Soc Esp Oftalmol 2009; 84: Shields JA, Shields CL, De Potter P: Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol. 1997; 115: Tabin G, Levin S, Snibson G. Late recurrences and the necessity for long-term follow-up in corneal and conjunctival intraepithelial neoplasia. Opthalmology 1997; 104(3): Frucht-Pery J, Sugar J, Baum J, Stuphin J. Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology 1997 Dec; 104(12): Shields CL, Naseripour M, Shields JA, Eagle RC Jr. Topical mitomycin-c for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology 2002 Nov; 109(11): Yamamoto N, Ohmura T, Suzuki H, Shirasawa H. Successful treatment with 5-fluoracil of conjunctival intraepithelial neoplasia refractive to mitomycin-c. Ophthalmology 2002; 109: Holcombe D, Lee A. Topical interferon Alfa-2b for the treatment of recalcitrant ocular surface squamous neoplasia. American Journal of Ophthalmology 2006; 142: Díaz-Valle D, Benítez-del-Castillo JM, Díaz-Valle T, Poza-Morales Y, Arteaga-Sánchez A. Treatment with topical interferon alone in severe conjunctivo-corneal neoplasia. Arch Soc Esp 2005; 80: Toledano Fernández N, García Sáenz S, Díaz Valle D, Arteaga Sánchez A, Segura Bedmar M, Lorenzo Giménez S, Cortés Lambea L. Interferon alfa-2b treatment in selected cases of recurrent conjunctival intraepithelial neoplasia. Arch Soc Esp Oftalmol May; 78(5): Auw-Haedrich C, Sundmacher R, Freudenberg N, et al. Expression of p63 in conjunctival intraepithelial neoplasia and squamous cell carcinoma. Graefes Arch Clin Exp Ophthalmol. 2006; 244: Scott IU, Karp CL, Nuovo GJ. Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. Ophthalmology 2002; 109: Napora C, Cohen EJ, Genvert GI, Presson AC, Arentsen JJ, Eagle RC, et al. Factors associated with conjunctival intraepithelial neoplasia: a case control study. Ophthalmic Surg 1990; 21: Schechter BA, Schrier A, Nagler RS, Smith EF, Velasquez GE. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Cornea. 2002: 21(1): Karp CL, Galor A, Chhabra S, Barnes SD, Alfonso EC. Subconjunctival/perilesional recombinant interferon a2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology Dec; 117(12): Boehm MD, Huang AJ. Treatment of recurrent corneal and conjunctival intraepithelial neoplasia with topical interferon alpha 2b. Ophthalmology. 2004; 111 (9): Fuchsluger TA, Hintschich C, Steuhl KP, Meller D. Adjuvant topical interferon- alpha- 2b treatment in epithelial tumors of the ocular surface. Ophthalmology. 2006; 103 (2): First author: Luis Fernández-Vega Cueto, MD Centro de Oftalmología Barraquer Spain