Topical Mitomycin C for the Treatment of Conjunctival and Corneal

Epithelial Dysplasia and Neoplasia

MATTHEW W. WILSON, MD, JOHN L. HUNGERFORD, FRCS, FRCOPHTH, SHEENA M. GEORGE, FRCOPHTH, AND STEVEN A. MADREPERLA, MD, PHD

• PURPOSE: To evaluate the efficacy of topical mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia. • METHODS: Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were re­viewed retrospectively. Patients with either multi­ple recurrences or extensive ocular surface in­volvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment. • RESULTS: With topical mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical mitomycin C therapy and excision of resid­ual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical mitomycin C therapy was associated with transitory ocular discomfort,

Accepted for publication Jan 16, 1997. From the Ocular Oncology Unit, St Bartholomew's Hospital, and

Moorfields Eye Hospital, London, UK. Correspondence to Matthew W. Wilson, MD, University of Colorado

Health Science Center, Department of Ophthalmology, Campus Box B204, 4200 E Ninth Ave, Denver, CO 80262; fax: (303) 315-5644; e-mail: wilsonm@jove.UCHSC.edu

No reprints are available.

conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy. • CONCLUSION: In this small series of eyes, topical mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia.

CONJUNCTIVAL AND CORNEAL EPITHELIAL DYS-plasia and neoplasia are uncommon lesions of uncertain malignant potential.1'3 Clinical ex­

amination often discloses a poorly demarcated tumor. Local excision remains standard therapy for the management of conjunctival and corneal epithelial dysplasia and neoplasia. Difficulty in obtaining clear surgical margins leads to recurrence rates of 25% to 53%.u Adjunctive therapy may prevent repeated

See also pp 381-383 and 397-399.

excisions and associated scarring. Cryotherapy,4,5 beta radiation,6,7 topical urea,8 and immunotherapy9 have been used to curtail recurrent disease. Diffuse con­junctival and corneal disease precludes complete surgical excision without significant ocular morbidity.

Both topical 5-fluorouracil 1%10 and topical mito­mycin C 0.02%u have been used effectively in the treatment of conjunctival and corneal epithelial dys­plasia and neoplasia. Topical therapy provides treat­ment to the entire ocular surface. Surgical trauma is avoided, and repeated applications are possible. We report seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia treated with topical mitomycin C 0.04%-

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PATIENTS AND METHODS

SEVEN EYES OF SEVEN PATIENTS WITH CONJUNCTIVAL and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% between January 1995 and July 1996. The patients' charts were reviewed retrospectively. Patients who had had multiple attempts at local excision with associated conjunctival and corneal scarring or who had diffuse ocular surface involvement were selected for treat­ment with topical mitomycin C. Two patients had previously received beta radiation and cryotherapy as adjunctive therapies. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy with mitomycin C. All surgical wounds were allowed to epithelialize completely before mitomycin C was started.

Patients were instructed to instill one drop of topical mitomycin C 0.04% four times daily in the affected eye for 7 days. In the eye receiving treatment, a collagen punctal plug was placed in the inferior canaliculus to limit toxicity to the nasolacrimal drain­age system and to decrease systemic absorption. Patients were reviewed 14 days later to assess treat­ment response. Patients whose disease had regressed discontinued therapy. Patients with persistent disease began another week of therapy and were reexamined in another 14 days. In the eye that received treatment, a collagen plug was placed as before.

CASE REPORTS

• CASE l: A 68-year-old man was diagnosed with conjunctival and corneal epithelial dysplasia of the right eye in 1987. Three attempts at local excision were made before his referral to the Ocular Oncology Service at St Bartholomew's Hospital in January 1993. Examination at that time disclosed a best-cor­rected visual acuity of RE, 6/9 (20/30) and LE, 6/6 (20/20). Slit-lamp biomicroscopy showed a raised gelatinous mass with telangiectatic vessels involving the temporal bulbar conjunctiva and limbus. The left eye was normal. An excisional biopsy of the lesion was performed, and 30 Gy of strontium-90 beta radiation was administered topically as an adjunct. A local recurrence in August 1993 was treated similarly

•m *

FIGURE 1. Patient 1. Conjunctival biopsy from August 1993 showing moderate dysplasia (X80).

(Figure 1). Recurrences in February 1994 and June 1994 were treated with triple-freeze thaw cryotherapy.

A recurrence extending from the 10- to 5-o'clock positions was noted in the right eye in January 1995 (Figure 2). Topical mitomycin C 0.04% four times daily for 7 days was started. There was persistent disease present at 2 and 4 weeks, and additional topical mitomycin C was prescribed (Figure 3). At 6 weeks, marked regression of his disease was noted, and mitomycin C was discontinued. Twenty-one days of topical mitomycin C 0.04% had been administered. Follow-up examinations showed complete regression of his disease (Figure 4). Sixteen months after treat­ment, he was without conjunctival and corneal epithelial dysplasia and had maintained 6/6 (20/20) visual acuity in the right eye.

Side effects associated with topical mitomycin C included transient conjunctival injection, tearing, photophobia, and punctate epithelial kerafopathy of

304 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 1997

FIGURE 2. Patient 1. Pretreatment external photograph of the right eye, showing recurrent conjunctival and corneal epithelial dysplasia extending from the 10-o'clock to 5-o'clock positions.

FIGURE 3. Patient 1. Nasal conjunctiva of the right eye after 14 days of treatment with topical mitomycin C. Residual tumor is present.

the right eye. Side effects resolved within 1 week of his discontinuing topical mitomycin C drops.

• CASE 7: An 82-year-old man was seen in March

1996 with a 9-month history of a limbal lesion in the right eye. His ocular history was remarkable for a central retinal artery occlusion in the right eye. His best-corrected visual acuity was RE, no light percep-

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FIGURE 4. Patient 1. External photograph of the right eye with complete clinical regression of conjunctival and corneal epithelial dysplasia.

tion and LE, 6/9 (20/30). In the right eye, an elevated vascular mass arose from the nasal limbus and extended across the cornea, obscuring the visual axis (Figure 5). It measured 5 x 5 mm. A prominent feeder vessel was present. An incisional biopsy showed carcinoma in situ. One drop of topical mitomycin C 0.04% was prescribed four times a day for 7 days. Two weeks later, the lesion persisted, and a second course of topical mitomycin C was prescribed. The patient subsequently required hospitalization for congestive heart failure and was not seen for 1 month. At that time, the lesion had diminished in size (to 2.5 X 1 mm). A third course of topical mitomycin C was administered. When the patient was examined 2 weeks later, the lesion had completely regressed (Figure 6). He was without recurrent conjunctival and corneal epithelial neoplasia 2 months after treatment. His only reported side effect was transient ocular discomfort.

RESULTS

SIX EYES OF SEVEN PATIENTS HAD A COMPLETE CLINICAL response to topical mitomycin C 0.04%. Patient 5 had

a partial response; the dysplastic lesion in his left eye decreased in size before a residual focus of tumor was excised and adjunctive cryotherapy applied. The seven cases are summarized as follows (Table).

Differing severities of conjunctival and corneal epithelial dysplasia and neoplasia were treated. Three patients had moderate to severe dysplasia of the conjunctiva and cornea, and four patients had carci­noma in situ. Four patients had had multiple excisiqn-al biopsies attempted previously. Patient 1 had twice received adjunctive beta radiation with a strontium-90 applicator. Further recurrences of his tumor had been treated with triple-freeze thaw cryotherapy. Patient 2 also had had previous cryotherapy for recurrent dysplasia after attempted excision. Patient 5 had had only one previous attempt at excision before initial examination.

On initial examination, Patients 3 and 7 displayed untreated disease. The diffuse nature of their lesions precluded excision without risking significant ocular surface morbidity. An incisional biopsy of each lesion was performed to confirm the suspected clinical diagnosis. The lesions were allowed to epithelialize before treatment with topical mitomycin C 0.04% was initiated.

Variable treatment responses were observed among

306 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 1997

FIGURE 5. Patient 7. Pretreatment external photpgraph of the right eye, showing the tumor.

the seven eyes of the seven patients. Four patients required 21 days of topical mitomycin C 0.04% drops for their conjunctiva! and corneal tumors to regress completely. Patient 4 required only 14 days of topical mitomycin C in the right eye before complete clinical regression of his tumor occurred. Patient 6 discontin­ued topical mitomycin C 0.04% after 4 days because of pain and redness qf the treated eye. She noted at that time that the growth on her right eye had disappeared. Ten days later, we confirmed that the lesion had completely regressed.

All patients experienced transitory side effects in the treated eye during therapy with topical mitomycin C 0.04%. These included conjunctival injection, tearing, photpphobia, and punctate epithelial kera-topathy. All side effects resolved within 1 week of discontinuing topical mitomycin C except for punc­tate epithelial keratopathy in the left eye of Patient 5 that persisted for 3 weeks after cessation of ther­apy. No permanent reduction in visual acuity was observed.

Follow-up after discontinuation of topical mitomy­cin C 0.04% and excision of residual disease ranged from 2 to 16 months (average, 9 months; SD, 4.3 months). All patients were without recurrence of conjunctival and corneal epithelial dysplasia and neoplasia.

DISCUSSION

SIX EYES OF SEVEN PATIENTS WITH CONJUNCTIVAL AND corneal epithelial dysplasia and neoplasia were suc­cessfully managed with topical mitomycin C 0.04%. Mitomycin C is a chemotherapeutic antibiotic isolat­ed from Streptomyces caespitosus. Its molecular struc­ture contains urethane and quinone groups, each capable of covalently reacting with DNA. Intracellu-lar enzymatic reduction of its quinone ring and its methoxy group permit mitomycin C to function as an alkylating agent. Cross-linkage of DNA at the N6

position of adenine and the O2 and N2 positions of guanine inhibit DNA synthesis. Mitomycin C also causes breakage of single-stranded DNA. Its actions are most prominent during the late Gj and S phases of the cell cycle.12

Alkylators most closely parallel radiation in their mechanism of action. They are non-cell-cycle specif­ic. Rapidly dividing cells are the most sensitive. Cell death follows first-order or pseudo-first-order kinetics in that a fixed linear-dose increment generates a constant fractional cell kill. The maximum likelihood of eradicating all cancer cells is achieved when the highest possible doses are used against the smallest possible tumor load.13,14 This property of mitomycin C, combined with the findings of Ando and associ-

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FIGURE 6. Patient 7. External photograph of the right eye, showing regression of the tumor after 21 days of treatment with topical mitomycin C.

ates15 that topical mitomycin C 0.04% is relatively nontoxic to an intact surface epithelium, compelled us to use a 0.04% concentration of mitomycin C.

The use of mitomycin C as a systemic chemothera-peutic agent is limited by its rapid hepatic metabolism and its toxicity. Mitomycin C has been used topically to treat transitional cell carcinoma of the bladder by intravesicular instillation. Topical mitomycin C has become an increasingly familiar part of the ophthal­mic pharmacopeia. It has potent antiproliferative effects on subconjunctival fibroblasts and modulates the wound-healing response.16 Mitomycin C is used as an adjunct in the surgical management of pterygi-um17,18 and glaucoma19 and has also been used as a modulator of corneal healing after excimer laser refractive surgery.20 Finger and associates21 used topi­cal mitomycin C 0.04% four times daily for 28 consecutive days to chemoreduce a malignant mela­noma of the conjunctiva before excision. This was the first case report of using topical mitomycin C to treat neoplasms of the conjunctival and corneal surfaces.21

Reported complications from topical mitomycin C use include scleral ulceration,22'24 necrotizing scleri-tis,25 perforation,22,25 iridocyclitis,22'24 cataract,24 glau­coma,24,25 scleral calcification,22'25 and loss of the eye.24

These reports are limited to the application of mito­mycin C to bare sclera. Rubinfeld and associates26

correlated toxicity with cumulative dose. We did not observe such severe side effects. Tran­

sient side effects were reported in the treated eye by all seven of our patients and included transient ocular discomfort, conjunctival injection, tearing, and pho­tophobia. These complaints intensified as therapy continued and most likely correlated with tumor desquamation. Punctate corneal staining with fluo-rescein was also noted. No scarring or tear film abnormalities were observed. We believe an intact epithelial surface limited toxicity to deeper ocular structures. Additionally, our patients were sup­plied with only 1 week of topical mitomycin C at a time. External diseases such as Sjogren syndrome, keratoconjunctivitis sicca, ocular rosacea, atopic keratoconjunctivitis, and herpes simplex keratitis may exacerbate side effects.26

A collagen punctal plug was placed in the inferior canaliculus of each eye before each 7-day treatment to limit toxicity to the nasolacrimal drainage system and to decrease systemic absorption. This did not prevent access to the superior punctum. Systemic toxicity and damage to the nasolacrimal drainage system were not

308 AMERICAN JOURNAL OF OPHTHALMOLOGY SEPTEMBER 1997

TABLE. Patients With Conjunctival and Corneal Epithelial Dysplasia and Neoplasia Treated With Topical Mitomycin C

Patient No., Eye, Age (yrs), Sex

1,RE, 68, M

2. LE. 56, M

3. LE, 73., M

4. RE, 83, M

5, LE, 50, M

6. RE, 38, F

7, RE, 82, M

Treatment Before MMC

Biopsy x 5, Str-90 x 2, cryo x 2

Biopsy x 2, cryo x 2

Biopsy

Biopsy x 2

Biopsy

Biopsy < 4

Biopsy

MMC - mitomycin C; Str-90

Histopathologic Findings Before

MMC

Moderate to severe dysplasia

Moderate to severe dysplasia

Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

Carcinoma in situ

Duration of Topical

MMC (days)

21

21

21

1*

35

4

21

Clinical Response

Complete resolution

Complete resolution

Complete resolution

Complete resolution

Partial resolution

Complete resolution

Complete resolution

Side Effects of MMC

Conjunctival inflammation, tearing, photophobia, punctate epithelial keratopathy

Pain, conjunctival inflammation, tearing, photophobia

Pain, conjunctival inflammation, tearing

Pain

Pain, conjunctival inflammation, tearing, photophobia, punctate epithelial keratopathy

Pain, conjunctival inflammation

Pain

= 30 Gy of strontium 90 beta radiation; cryo = triple-freeze thaw cryotherapy.

Follow-up After Completion of MMC (mos)

16

10

10

9

6

8

2

observed. (Safe usage of mitomycin C in pregnant women has not been established. Teratologic changes have been noted in animal studies.16)

As shown by our patients, tumor sensitivity to alkylating agents is variable. Four patients required 3 weeks of topical mitomycin C 0.04%. Patient 4 responded after 2 weeks, and Patient 6 had complete regression after 4 days. Patient 5 had 5 weeks of therapy and still required local excision for residual disease. The treatment of Patient 7 was interrupted by an unrelated illness, but he still showed a dramatic response to mitomycin C.

Heterogeneous responses of tumor cells to alkyla­ting agents frequently select for more resistant clones. Continuing investigations support the claim that cross-linking alone does not account for cell death. A battery of oncogenes, including tumor suppressor genes, survival genes, and cell-cycle checkpoint genes, governs cytotoxic sensitivity. Intermittent therapy prevents damage to slower-growing cells, allowing time for them to repair their DNA.13,14 Limbal stem-cell depletion may be avoided by alternate-week therapy.

Patients 3 and 5 had ocular histories remarkable for

herpes simplex keratitis involving the symptomatic eye. An association between herpes simplex and conjunctival and corneal epithelial dysplasia and neoplasia has been suggested but not proved.27 Biopsy specimens were not examined for the herpes simplex virus. No conclusions can be made regarding this possible treatment variable. Furthermore, we cannot exclude the possibility that these episodes of herpes simplex were not a manifestation of dysplastic or neoplastic disease. Patient 5 had also received system­ic chemotherapy for the treatment of non-Hodgkin lymphoma. He was in remission and immunpcompe-tent at the time of diagnosis. The effects of his previous medical history are not known.

We have used topical mitomycin C to treat only epithelial disease. No invasive cases of squamous cell carcinoma have been treated by topical mitomycin C. We are concerned that topical administration onto an intact epithelial surface may not permit adequate penetration of mitomycin C into subepithelial tissues. Caution is recommended in treating invasive disease, especially that involving the scjera. Additionally, the ability of mitomycin C to treat patients with heredi­tary disorders of DNA repair, such as xeroderma

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pigmentosum, is suspect. Alkylation of DNA in noncancerous cells may predispose to new tumor formation in these patients.

Our seven patients support the findings of Frucht-Pery and Rozenman,11 who used topical mitomycin C 0.02% to treat four patients with corneal epithelial dysplasia and neoplasia involving the visual axis. Their patients received 10 to 22 days of topical mitomycin C 0.02% four times daily without interrup­tion. Reported side effects were similar to those of our patients. No permanent sequelae were noted. Further study is needed to establish an exact treatment protocol for the administration of topical mitomycin C in the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Given the variables in tumor response, simple clinical observation— monitoring tumor regression and side effects—may prove to be the optimal management. Resistant cases may require alternative therapy with either surgery or other adjunctive measures.

The ability of mitomycin C to prevent long-term recurrences has yet to be determined. Our longest follow-up is 16 months. If conjunctival and corneal epithelial dysplasia and neoplasia are related to actinic or viral exposure,27'29 diffuse ocular surface disease may exist and new foci of tumor may arise. Topical mitomycin may eliminate epithelial cells with solar-induced or virally induced DNA damage, thus pre­venting new tumor formation.

In a small series of eyes, topical mitomycin C 0.04% appears to be effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia. Topi­cal mitomycin C may be used adjunctively after biopsy when residual tumor is visible clinically or as initial therapy in treating recurrent disease.

REFERENCES

1. Pizzarello LD, Jakobiec FA. Bowen's disease of the conjuncti­va: a misnomer. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham: Aesculapius, 1978:553-571.

2. Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmolo­gy 1986;93:176-183.

3. Waring GO III, Roth AM, Ekins MB. Clinical and patholog­ical description of 17 cases of corneal intraepithelial neopla­sia. Am J Ophthalmol 1984;97:547-559.

4. Fraunfelder FT, Wingfield D. Therapy of intraepithelial

310 AMERICAN JOURNAL

epitheliomas and squamous cell carcinoma of the limbus. Trans Am Ophthalmol Soc 1980;79:290-300.

5. Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctival tumors and squamous cell carcinomas. Am J Ophthalmol 1983;95:359-363.

6. Elkon D, Constable WC. The use of strontium-90 in the treatment of carcinoma in situ of the conjunctiva. Am J Ophthalmol 1979;87:84-86.

7. Jones DB, Wilhelmus KR, Font RL. Beta radiation of recurrent corneal intraepithelial neoplasia. Trans Am Oph­thalmol Soc 1991;89:285-301.

8. Danopoulus ED, Danopoulou IE, Liarikos SB, Merkuris KM. Effects of urea treatment in malignancies of the conjunctiva and cornea. Ophthalmologica 1979;178:198-203.

9. Ferry AP, Meltzer MA, Taub RN. Immunotherapy with dinitrochlorobenzene (DNCB) for recurrent squamous cell tumor of conjunctiva. Trans Am Ophthalmol Soc 1976;74: 154-171.

10. Yeatts RP, Ford JG, Stanton CA, Reed JW. Topical 5-fluorouracil in treating epithelial neoplasia of the conjunctiva and cornea. Ophthalmology 1995;102:1338-1344.

11. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117:164— 168.

12. Calabresi P, Parks RE. Antiproliferative agents and drugs used for immunosuppression. In: Gilman AG, Rail TW, Nies AS, Taylor P, editors. Goodman and Oilman's the pharma­cological basis of therapeutics, 8th ed. New York: Pergamon, 1990:1247-1248.

13. Workman P, Lewis AD, Caseate F. Alkylating agents and related drugs. In: Peckham M, Pinedo HM, Veronesi U, editors. Oxford textbook of oncology. Volume 1. Oxford, UK: Oxford University Press, 1995;495-504-

14- Peters GF. Antimetabolites. In: Peckham M, Pinedo HM, Veronesi U, editors. Oxford textbook of oncology. Volume 1. Oxford, UK: Oxford University Press, 1995:530-534-

15. Ando H, Ido T, Kawai Y, et al. Inhibition of corneal epithelial wound healing: a comparative study of mito­mycin C and 5-fluorouracil. Ophthalmology 1992;99: 1809-1814.

16. Yamamoto T, Varani J, Soong HK, Lichter PR. Effects of 5-fluorouracil and mitomycin C on cultured rabbit subcon-junctival fibroblasts. Ophthalmology 1990;97:1204-1210.

17. Kunitomo N, Mori S. Studies on the pterygium, part IV: a treatment of the pterygium by mitomycin C instillation. Nippon Ganka Gakkai Zasshi 1963;67:601-607.

18. Singh G, Wilson MR, Foster CS. Mitomycin eye drops as treatment for pterygium. Ophthalmology 1988;95:813-821.

19. Palmer SS. Mitomycin as adjunct chemotherapy with trabec-ulectomy. Ophthalmology 1991;98:317-321.

20. Talamo JH, Gollamudi S, Green WR, et al. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol 1991;109:1141-1146.

21. Finger PT, Milner MS, McCormick SA. Topical chemothera­py for conjunctival melanoma. Br J Ophthalmol 1993;77: 751-753.

22. Fukamachi Y, Hikita N. Ocular complication following pterygium operation and instillation of mitomycin C. Folia Ophthalmol Jpn 1981;32:197-201.

23. Yamanouchi U, Takaku I, Tsuda N, et al. Scleromalacia presumably due to mitomycin C instillation after pterygium excision. Jpn J Clin Ophthalmol 1979;33:139-144.

OF OPHTHALMOLOGY SEPTEMBER 1997

24. Yamanouchi U. A case of scleral calcification due to mitomy-cin C instillation after pterygium operation. Folia Ophthal-mol Jpn 1978;29:1221-1225. Yamanouchi U, Mishima K. Eye lesions due to mitomycin C instillation after pterygium operation. Folia Ophthalmol Jpn 1967;18:854-861. Rubinfeld RS, Pfister RR, Stein RM, et al. Serious complica­tions of topical mitomycin C after pterygium surgery. Oph­thalmology 1992;99:1647-1654.

27. Lee GA, Williams G, Hirst LW, Green AC. Risk factors in

25

26

28.

29.

the development of ocular surface epithelial dysplasia. Oph­thalmology 1994;101:360-364-McDonnell JM, Mayr AJ, Martin WJ. DNA of human papillomavirus type 16 in dysplastic and malignant lesions of the conjunctiva and cornea. N Engl J Med 1989;320: 1442-1446. 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;33:184-189.

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