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Research Letters |

Rapid Response of Refractory Ocular Surface Dysplasia to Combination Treatment With Topical All- trans Retinoic Acid and Interferon Alfa-2b FREE

Brent Skippen, MBBS, MPH; Hughie H. Tsang, MB, BS, MMedStats; Nagi N. Assaad, MBBS, BSc(Med), MBiomedE,  FRANZCO; Minas T. Coroneo, MD, MS, MSc, FRACS, FRANZCO
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology, University of New South Wales and Prince of Wales Hospital, Randwick, New South Wales, Australia.


Arch Ophthalmol. 2010;128(10):1368-1369. doi:10.1001/archophthalmol.2010.241.
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Topical treatments of ocular surface dysplasia are attractive because these conditions tend to recur.13 Traditional surgical procedures such as excision and cryotherapy are destructive and can have long-term consequences, particularly with limbal involvement.2,3 Interferon alfa-2b is a well-tolerated and generally efficacious topical therapy option for ocular surface dysplasia.13 The combination of interferon with retinoic acid may be a useful alternative for treating interferon-unresponsive lesions.

A 64-year-old woman had a history of long-term exposure to sunlight. On examination, a keratinized lesion at her left temporal limbus was noted, extending from the 3-o’clock position to the 5-o’clock position and measuring 3.5 × 2.0 mm. Best-corrected visual acuity was 6/5 OU.

A clinical diagnosis of limbal dysplasia was made and treatment was commenced with topical all- trans retinoic acid (ATRA), 0.01%, 1 eyedrop applied every second day. The lesion grew slowly and the patient was reassessed after 9 months of treatment with topical ATRA. The clinical diagnosis was confirmed (Figure, A) and the patient was treated with 2 intralesional injections of 3 × 106 IU of recombinant interferon alfa-2b (Schering Plough, Kenilworth, New Jersey) in 0.5 mL, 2 months apart, followed by topical interferon alfa-2b (1 × 106 IU/mL) 4 times a day.

Place holder to copy figure label and caption
Figure.

A dysplastic lesion was noted at the left temporal limbus at the initial visit (A), and the limbal lesion had resolved 1 month following combined treatment with topical interferon and retinoic acid (B).

Graphic Jump Location

Three months later, the lesion appeared larger despite continuous use of topical interferon alfa-2b. The patient was reluctant to undergo surgery, and it was decided to continue with combined topical interferon alfa-2b (1 × 106 IU/mL 4 times a day) and ATRA, 0.01% (1 eyedrop applied every second day). After 1 month of combination treatment, the lesion had totally resolved (Figure, B). Furthermore, limbal architecture had returned to normal in the previously affected area.

Combination treatment was continued for a further 1 month, with no lesion visible. Unfortunately, the lesion had returned on follow-up 3 months later, so the patient elected to undergo surgery. A wide excision specimen was sent for histopathologic analysis. This demonstrated a partial-thickness lesion positive for cornea and conjunctiva intraepithelial neoplasia with no evidence of invasive squamous cell carcinoma. The patient has remained disease free for longer than 2 years.

Topical interferon was first described by Maskin1 in 1994 as being effective in the treatment of ocular neoplasia. A limited number of cases in the literature also show the cytostatic effect of ATRA on ocular surface dysplasia.4

Our early experience with topical ATRA alone was consistent with early reports of effectiveness, with no response occurring in certain patients. Our early experience with topical interferon alfa-2b demonstrated a more consistent clinical response, and recent studies have documented an 80% treatment efficacy using topical interferon alfa-2b.2 Mitomycin C and fluorouracil are alternative topical therapies for ocular surface dysplasia. However, interferon has fewer ocular adverse effects compared with these topical chemotherapeutic agents.2 Retinoic acid is known to irritate the conjunctiva in higher doses.4

In our patient, neither ATRA nor interferon alfa-2b alone was effective in slowing growth of the ocular lesion. Longer treatment with interferon alfa-2b may have led to a better response. The rapid clinical response to the combined treatment with topical interferon alfa-2b and ATRA seems remarkable. However, previous studies have described the synergistic effects of interferon alfa-2b and ATRA in combination, both in vitro and in vivo. These same studies, although not of an eye or eye model, reported that ATRA can permit growth inhibition by interferons in interferon-unresponsive cells.5

Prospective studies with more patients and longer follow-up are needed to confirm the treatment efficacy and safety profile of this combination therapy as a well-tolerated alternative to topical mitomycin C and fluorouracil. Appropriate further studies may reveal a benefit for both dysplastic and neoplastic lesions.

Correspondence: Dr Coroneo, Department of Ophthalmology, University of New South Wales and Prince of Wales Hospital, Randwick, New South Wales, Australia 2031 (coroneom@optusnet.com.au).

Financial Disclosure: None reported.

Maskin  SL Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol 1994;112 (9) 1145- 1146
PubMed Link to Article
Sepulveda  RPe’er  JMidena  ESeregard  SDua  HSSingh  AD Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2010;94 (5) 532- 535
PubMed Link to Article
Schechter  BAKoreishi  AFKarp  CLFeuer  W Long-term follow-up of conjunctival and corneal intraepithelial neoplasia treated with topical interferon alfa-2b. Ophthalmology 2008;115 (8) 1291- 1296, 1296.e1
PubMed Link to Article
Herbort  CPZografos  LZwingli  MSchoeneich  M Topical retinoic acid in dysplastic and metaplastic keratinization of corneoconjunctival epithelium. Graefes Arch Clin Exp Ophthalmol 1988;226 (1) 22- 26
PubMed Link to Article
Kolla  VWeihua  XKalvakolanu  DV Modulation of interferon action by retinoids: induction of murine STAT1 gene expression by retinoic acid. J Biol Chem 1997;272 (15) 9742- 9748
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

A dysplastic lesion was noted at the left temporal limbus at the initial visit (A), and the limbal lesion had resolved 1 month following combined treatment with topical interferon and retinoic acid (B).

Graphic Jump Location

Tables

References

Maskin  SL Regression of limbal epithelial dysplasia with topical interferon. Arch Ophthalmol 1994;112 (9) 1145- 1146
PubMed Link to Article
Sepulveda  RPe’er  JMidena  ESeregard  SDua  HSSingh  AD Topical chemotherapy for ocular surface squamous neoplasia: current status. Br J Ophthalmol 2010;94 (5) 532- 535
PubMed Link to Article
Schechter  BAKoreishi  AFKarp  CLFeuer  W Long-term follow-up of conjunctival and corneal intraepithelial neoplasia treated with topical interferon alfa-2b. Ophthalmology 2008;115 (8) 1291- 1296, 1296.e1
PubMed Link to Article
Herbort  CPZografos  LZwingli  MSchoeneich  M Topical retinoic acid in dysplastic and metaplastic keratinization of corneoconjunctival epithelium. Graefes Arch Clin Exp Ophthalmol 1988;226 (1) 22- 26
PubMed Link to Article
Kolla  VWeihua  XKalvakolanu  DV Modulation of interferon action by retinoids: induction of murine STAT1 gene expression by retinoic acid. J Biol Chem 1997;272 (15) 9742- 9748
PubMed Link to Article

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