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Mitomycin C Treatment of Conjunctival Intraepithelial Neoplasia
EDITORIAL Mitomycin C Treatment of Conjunctival Intraepithelial Neoplasia HANS E. GROSSNIKLAUS, MD, AND THOMAS M. AABERG, SR, MD
NTRAEPITHELIAL NEOPLASIA OF THE CONJUNCTIVA,
including dysplasia and carcinoma in situ, is relatively common in clinical ophthalmic practice, representing approximately one third of all surgically excised acquired epithelial lesions of the conjunctiva.1 Dysplasia progresses through a sequential series, increasing in severity from mild through severe dyspla' sia and finally carcinoma in situ. Dysplasia and carcinoma in situ are thought to be precursor lesions to invasive squamous cell carcinoma,2 the most com' mon primary malignancy of the conjunctiva.1,3,4 For' tunately, conjunctival squamous cell carcinoma is a low-grade malignancy,1 with only nine tumor-related deaths documented in the literature.4 Most dysplasias do not progress to squamous cell carcinoma because many are completely excised, and there is involution in approximately 30% to 45% of incompletely excised lesions.5,6 A small percentage of apparently completely excised lesions recur.5,7 One conjunctival intraepithe lial neoplastic lesion was reported to have spontane ously regressed.7 It is possible that the host immune/ inflammatory response plays a role in the regression of conjunctival intraepithelial neoplasia, especially with regard to the presence of human Papillomavirus in these lesions8,9 and with regard to the association of human immunodeficiency virus infection in young
Accepted for publication March 25, 1997. From the Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia. Correspondence to Hans E. Orossniklaus, MD, Department of Oph thalmology, Emory University School of Medicine, 1327 Clifton Rd NE, Atlanta, GA 30322; fax: (404) 778-4143; e-mail: [email protected] No reprints are available.
VOL.124,
No. 3
patients, who are prone to develop conjunctival intraepithelial neoplasia.10 See also pp 303-311 and 397-399.
There are two main clinicopathologic variants of conjunctival intraepithelial neoplasia.11,12 One is the actinic form. This lesion occurs at the limbus in the interpalpebral fissure, most often in men in their sixth or seventh decades. There is solar elastosis of the underlying substantia propria. This lesion may be seen in association with a pinguecula or pterygium. The lesion is almost always cured by surgical excision, even though dysplastic cells often extend onto the cornea and are not completely removed. This lesion probably accounts for the high cure rate in most patient series, even when the lesion is technically incompletely excised.5,6 The second clinicopathologic variant is diffuse intraepithelial neoplasia. This variant, although less common than the actinic variant, poses a greater clinical challenge than the first variant does. Patients with this second variant may have diffuse, indistinct involvement of the bulbar and palpebral conjunctiva, often resulting in a "masquerade syndrome" of chron ic unilateral blepharoconjunctivitis. Sometimes pa tients with the diffuse form of conjunctival intraepi thelial neoplasia exhibit symblepharon.13 The diffuse variant of conjunctival intraepithelial neoplasia is difficult to treat largely because the lesion has no distinct clinical borders and because involved tissue may be clinically indistinguishable from uninvolved tissue. Patients with this form of the disease
EDITORIAL
381
are prone to having multiple recurrences and requir ing multiple surgeries. Adjuvant therapies have been utilized with varying degrees of success in these difficult cases. Radiotherapy, including strontium-9014 and gamma radiation,15 is associated with between a 2% and 47% recurrence rate.4 Complications of radiotherapy include dry eye, cataract, telangiectasis, scarring, scleral ulceration, and corneal rupture.16 Cryotherapy of tissue surrounding the site of surgical excision has been used.17 Cryotherapy presumably initially destroys cells by its thermal effect and then by ischemic necrosis.4 Complications increase with ex tensive freezing, as would be needed to treat the indistinct borders of the diffuse variant of conjuncti val intraepithelial neoplasia. Dinitrochlorobenzene, thiotepa, 5-fluorouracil, and urea have been applied in difficult cases,1,418'20 although these agents need frequent applications and close monitoring. 4 This issue of THE JOURNAL includes two reports21,22 describing topical mitomycin C as a promising adju vant treatment for difficult cases of conjunctival intraepithelial neoplasia. Mitomycin C is an anticancer antibiotic isolated from the broth of Streptomj' ces caespitosus, which has been found to inhibit DNA synthesis and fibroblast proliferation.23,24 Specifics re garding the mechanism of action of mitomycin C as an alkylating agent are discussed in the article by Wilson, Hungerford, and associates.21 Mitomycin C has been reported as a possible topical treatment of ocular melanocytic neoplasia.25,26 Frucht-Pery and Rozenman27 first reported topical mitomycin C thera py for corneal intraepithelial neoplasia in 1994. Wilson, Hungerford, and associates21 extended this initial work and successfully treated six of seven patients with diffuse and often recurrent conjunctival intraepithelial neoplasia. They used topical 0.04% mitomycin C, one drop in the affected eye four times a day, with frequent reassessments.21 Successful treat ment occurred after 4 to 21 days of topical mitomycin C. Transient side effects included conjunctival injec tion, tearing, photophobia, and punctate epithelial keratopathy.21 Wilson, Hungerford, and associates21 note that applying topical mitomycin C onto an intact epithelium may not permit adequate penetra tion into subepithelial tissue; therefore, topical mito mycin C is probably not to be indicated for invasive squamous cell carcinoma. Heigle and associates22 confirm the results of Wilson, Hungerford, and asso 382
ciates in an accompanying brief report, although Heigle and associates used mitomycin C as threetimes-a-day rather than four-times-a-day therapy. Several important points should be emphasized about using mitomycin C as an adjuvant therapy for conjunctival intraepithelial neoplasia. First, surgical excision is still the primary treatment. Histopathologic documentation of the diagnosis should be made before mitomycin C therapy is begun; this might include multiple map biopsies in patients with diffuse disease. Second, patient selection is critical when deciding to use topical mitomycin C. Patients with multiple recurrences of conjunctival intraepithelial neoplasia, diffuse disease not amenable to complete surgical excision, or multiple treatment failures, and debilitated patients unable to tolerate a surgical proce dure, are likely candidates. Examination of a conjunc tival exfoliative cytologic specimen may be performed to confirm the diagnosis, especially in the latter group of patients. Patients need to be monitored carefully and given a limited supply of the drug because they will be self-administering an agent with numerous potential side effects. Punctal occlusion during ad ministration, as used by Wilson, Hungerford, and associates,21 is an appropriate recommendation. Pa tients with frankly invasive squamous cell carcinoma are probably not good candidates for topical mitomy cin C treatment. Finally, topical mitomycin C is not approved by the Food and Drug Administration for the treatment of conjunctival intraepithelial neopla sia, and patients should sign an informed consent form before beginning treatment. With these cau tions in mind, topical mitomycin C is an exciting new therapeutic option for the treatment of a select group of patients with conjunctival intraepithelial neoplasia.
REFERENCES 1. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults: a clinical and histopathologic review. Cornea 1987;6:78-116. 2. Grossniklaus HE, Cameron JD. Eye. In: Henson DE, Albores-Saavedra J, editors. Pathology of incipient neoplasia. Chapter 28. Philadelphia: W.B. Saunders, 1993:544-556. 3. Ash JE. Epibulbar tumors. Am ] Ophthalmol 1950;33: 1203-1219. 4. Thee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39:429-450.
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER 1997
5. Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmolo gy 1986;93:176-183. 6. Pizzarello LD, Jakobiec FA. Bowen's disease of the conjuncti va: a misnomer. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham, UK: Aesculapius, 1978:553-571. 7. Morsman CD. Spontaneous regression of a conjunctival intraepithelial neoplastic tumor. Arch Ophthalmol 1989; 107:1490-1491. 8. McDonnell PJ, McDonnell JM, Kessis T, Green WR, Shah KV. Detection of human papilloma virus type 6/11 DNA in conjunctival papillomas virus by DNA in situ hybridization with radioactive probes. Hum Pathol 1987;18:1115-1119. 9. McDonnell JM, McDonnell PJ, Mounts P, Wu TC, Green WR. Demonstration of papilloma virus capsid antigen in human conjunctival neoplasia. Arch Ophthalmol 1986;104: 1801-1805. 10. Karp CL, Scott IU, Chang TS, Pflugfelder SC. Conjunctival intraepithelial neoplasia: a possible marker for human immu nodeficiency virus infection? Arch Ophthalmol 1996;114: 257-261. 11. McLean IW, Burnier MN, Zimmerman LE, Jakobiec FA. Atlas of tumor pathology: tumors of the eye and ocular adnexa. Washington, DC: Armed Forces Institute of Patholo gy, 1994:55-59. 12. Mauriello JA, Napolitano J, McLean I. Actinic keratosis and dysplasia of the conjunctiva: a clinicopathologic study of 45 cases. Can J Ophthalmol 1996;30:312-316. 13. Odrich MG, Jakobiec FA, Lancaster WD, et al. A spectrum of bilateral squamous conjunctival tumors associated with human Papillomavirus type 16. Ophthalmol 1991;628—635. 14- Cezero L, Otero J, Aragon G, et al. Conjunctival intraepithe lial neoplasia and invasive squamous cell carcinomas treated with strontium-90. Radiother Oncol 1990;17:191-197. 15. Goldberg JR, Becker SC, Rosenbaum HD. Gamma radiation in the treatment of squamous cell carcinoma of the limbus. Am J Ophthalmol 1976;55:811-815.
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No. 3
16. Philipp W, Daxecker F, Langmayr J, Gottinger W. Spontane ous corneal rupture after strontium irradiation of a conjuncti val squamous cell carcinoma. Ophthalmologica 1987; 195: 113-118. 17. Peksayar G, Soyturk MK, Demiryont M. Long-term results of cryotherapy on malignant epithelial tumors of the conjuncti va. Am J Ophthalmol 1989;15:337-340. 18. Ferry AP, Meltzen MA, Taub RN. Immunotherapy with dinitrochlorobenzene (DNCB) for recurrent squamous cell tumor of conjunctiva. Trans Am Ophthalmol Soc 1976; 74: 154-171. 19. Danopoulos ED, Danopoulos IE, Liarikos SB, Merkuris KM. Effects of urea treatment in malignancies of the conjunctiva and cornea. Ophthalmologica 1979;178:198-203. 20. Yeatts RP, Ford JG, Stanton CA, Reed JW. Topical 5fluorouracil in treating epithelial neoplasia of the conjunctiva and cornea. Ophthalmology 1995;102:1338-1344. 21. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997;124:303-311. 22. Heigle TJ, Stulting RD, Palay DA. Treatment of recurrent conjunctival epithelial neoplasia with topical mitomycin C. Am J Ophthalmol 1997;124:397-399. 23. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 1991;98:314-321. 24- Parrish RK. Who should receive antimetabolites after filter ing surgery? Arch Ophthalmol 1992;110:1069-1071. 25. Finger PT, Milner MS, McCormick SA. Topical chemothera py for conjunctival melanoma. Br J Ophthalmol 1993;77: 751-753. 26. Frucht-Pery J, Pe'erJ. Use of mitomycin C in the treatment of conjunctival primary acquired melanosis with atypia. Arch Ophthalmol 1996;114:1261-1264. 27. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117:164-168.
EDITORIAL
383
NTRAEPITHELIAL NEOPLASIA OF THE CONJUNCTIVA,
including dysplasia and carcinoma in situ, is relatively common in clinical ophthalmic practice, representing approximately one third of all surgically excised acquired epithelial lesions of the conjunctiva.1 Dysplasia progresses through a sequential series, increasing in severity from mild through severe dyspla' sia and finally carcinoma in situ. Dysplasia and carcinoma in situ are thought to be precursor lesions to invasive squamous cell carcinoma,2 the most com' mon primary malignancy of the conjunctiva.1,3,4 For' tunately, conjunctival squamous cell carcinoma is a low-grade malignancy,1 with only nine tumor-related deaths documented in the literature.4 Most dysplasias do not progress to squamous cell carcinoma because many are completely excised, and there is involution in approximately 30% to 45% of incompletely excised lesions.5,6 A small percentage of apparently completely excised lesions recur.5,7 One conjunctival intraepithe lial neoplastic lesion was reported to have spontane ously regressed.7 It is possible that the host immune/ inflammatory response plays a role in the regression of conjunctival intraepithelial neoplasia, especially with regard to the presence of human Papillomavirus in these lesions8,9 and with regard to the association of human immunodeficiency virus infection in young
Accepted for publication March 25, 1997. From the Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia. Correspondence to Hans E. Orossniklaus, MD, Department of Oph thalmology, Emory University School of Medicine, 1327 Clifton Rd NE, Atlanta, GA 30322; fax: (404) 778-4143; e-mail: [email protected] No reprints are available.
VOL.124,
No. 3
patients, who are prone to develop conjunctival intraepithelial neoplasia.10 See also pp 303-311 and 397-399.
There are two main clinicopathologic variants of conjunctival intraepithelial neoplasia.11,12 One is the actinic form. This lesion occurs at the limbus in the interpalpebral fissure, most often in men in their sixth or seventh decades. There is solar elastosis of the underlying substantia propria. This lesion may be seen in association with a pinguecula or pterygium. The lesion is almost always cured by surgical excision, even though dysplastic cells often extend onto the cornea and are not completely removed. This lesion probably accounts for the high cure rate in most patient series, even when the lesion is technically incompletely excised.5,6 The second clinicopathologic variant is diffuse intraepithelial neoplasia. This variant, although less common than the actinic variant, poses a greater clinical challenge than the first variant does. Patients with this second variant may have diffuse, indistinct involvement of the bulbar and palpebral conjunctiva, often resulting in a "masquerade syndrome" of chron ic unilateral blepharoconjunctivitis. Sometimes pa tients with the diffuse form of conjunctival intraepi thelial neoplasia exhibit symblepharon.13 The diffuse variant of conjunctival intraepithelial neoplasia is difficult to treat largely because the lesion has no distinct clinical borders and because involved tissue may be clinically indistinguishable from uninvolved tissue. Patients with this form of the disease
EDITORIAL
381
are prone to having multiple recurrences and requir ing multiple surgeries. Adjuvant therapies have been utilized with varying degrees of success in these difficult cases. Radiotherapy, including strontium-9014 and gamma radiation,15 is associated with between a 2% and 47% recurrence rate.4 Complications of radiotherapy include dry eye, cataract, telangiectasis, scarring, scleral ulceration, and corneal rupture.16 Cryotherapy of tissue surrounding the site of surgical excision has been used.17 Cryotherapy presumably initially destroys cells by its thermal effect and then by ischemic necrosis.4 Complications increase with ex tensive freezing, as would be needed to treat the indistinct borders of the diffuse variant of conjuncti val intraepithelial neoplasia. Dinitrochlorobenzene, thiotepa, 5-fluorouracil, and urea have been applied in difficult cases,1,418'20 although these agents need frequent applications and close monitoring. 4 This issue of THE JOURNAL includes two reports21,22 describing topical mitomycin C as a promising adju vant treatment for difficult cases of conjunctival intraepithelial neoplasia. Mitomycin C is an anticancer antibiotic isolated from the broth of Streptomj' ces caespitosus, which has been found to inhibit DNA synthesis and fibroblast proliferation.23,24 Specifics re garding the mechanism of action of mitomycin C as an alkylating agent are discussed in the article by Wilson, Hungerford, and associates.21 Mitomycin C has been reported as a possible topical treatment of ocular melanocytic neoplasia.25,26 Frucht-Pery and Rozenman27 first reported topical mitomycin C thera py for corneal intraepithelial neoplasia in 1994. Wilson, Hungerford, and associates21 extended this initial work and successfully treated six of seven patients with diffuse and often recurrent conjunctival intraepithelial neoplasia. They used topical 0.04% mitomycin C, one drop in the affected eye four times a day, with frequent reassessments.21 Successful treat ment occurred after 4 to 21 days of topical mitomycin C. Transient side effects included conjunctival injec tion, tearing, photophobia, and punctate epithelial keratopathy.21 Wilson, Hungerford, and associates21 note that applying topical mitomycin C onto an intact epithelium may not permit adequate penetra tion into subepithelial tissue; therefore, topical mito mycin C is probably not to be indicated for invasive squamous cell carcinoma. Heigle and associates22 confirm the results of Wilson, Hungerford, and asso 382
ciates in an accompanying brief report, although Heigle and associates used mitomycin C as threetimes-a-day rather than four-times-a-day therapy. Several important points should be emphasized about using mitomycin C as an adjuvant therapy for conjunctival intraepithelial neoplasia. First, surgical excision is still the primary treatment. Histopathologic documentation of the diagnosis should be made before mitomycin C therapy is begun; this might include multiple map biopsies in patients with diffuse disease. Second, patient selection is critical when deciding to use topical mitomycin C. Patients with multiple recurrences of conjunctival intraepithelial neoplasia, diffuse disease not amenable to complete surgical excision, or multiple treatment failures, and debilitated patients unable to tolerate a surgical proce dure, are likely candidates. Examination of a conjunc tival exfoliative cytologic specimen may be performed to confirm the diagnosis, especially in the latter group of patients. Patients need to be monitored carefully and given a limited supply of the drug because they will be self-administering an agent with numerous potential side effects. Punctal occlusion during ad ministration, as used by Wilson, Hungerford, and associates,21 is an appropriate recommendation. Pa tients with frankly invasive squamous cell carcinoma are probably not good candidates for topical mitomy cin C treatment. Finally, topical mitomycin C is not approved by the Food and Drug Administration for the treatment of conjunctival intraepithelial neopla sia, and patients should sign an informed consent form before beginning treatment. With these cau tions in mind, topical mitomycin C is an exciting new therapeutic option for the treatment of a select group of patients with conjunctival intraepithelial neoplasia.
REFERENCES 1. Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults: a clinical and histopathologic review. Cornea 1987;6:78-116. 2. Grossniklaus HE, Cameron JD. Eye. In: Henson DE, Albores-Saavedra J, editors. Pathology of incipient neoplasia. Chapter 28. Philadelphia: W.B. Saunders, 1993:544-556. 3. Ash JE. Epibulbar tumors. Am ] Ophthalmol 1950;33: 1203-1219. 4. Thee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39:429-450.
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER 1997
5. Erie JC, Campbell RJ, Liesegang TJ. Conjunctival and corneal intraepithelial and invasive neoplasia. Ophthalmolo gy 1986;93:176-183. 6. Pizzarello LD, Jakobiec FA. Bowen's disease of the conjuncti va: a misnomer. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham, UK: Aesculapius, 1978:553-571. 7. Morsman CD. Spontaneous regression of a conjunctival intraepithelial neoplastic tumor. Arch Ophthalmol 1989; 107:1490-1491. 8. McDonnell PJ, McDonnell JM, Kessis T, Green WR, Shah KV. Detection of human papilloma virus type 6/11 DNA in conjunctival papillomas virus by DNA in situ hybridization with radioactive probes. Hum Pathol 1987;18:1115-1119. 9. McDonnell JM, McDonnell PJ, Mounts P, Wu TC, Green WR. Demonstration of papilloma virus capsid antigen in human conjunctival neoplasia. Arch Ophthalmol 1986;104: 1801-1805. 10. Karp CL, Scott IU, Chang TS, Pflugfelder SC. Conjunctival intraepithelial neoplasia: a possible marker for human immu nodeficiency virus infection? Arch Ophthalmol 1996;114: 257-261. 11. McLean IW, Burnier MN, Zimmerman LE, Jakobiec FA. Atlas of tumor pathology: tumors of the eye and ocular adnexa. Washington, DC: Armed Forces Institute of Patholo gy, 1994:55-59. 12. Mauriello JA, Napolitano J, McLean I. Actinic keratosis and dysplasia of the conjunctiva: a clinicopathologic study of 45 cases. Can J Ophthalmol 1996;30:312-316. 13. Odrich MG, Jakobiec FA, Lancaster WD, et al. A spectrum of bilateral squamous conjunctival tumors associated with human Papillomavirus type 16. Ophthalmol 1991;628—635. 14- Cezero L, Otero J, Aragon G, et al. Conjunctival intraepithe lial neoplasia and invasive squamous cell carcinomas treated with strontium-90. Radiother Oncol 1990;17:191-197. 15. Goldberg JR, Becker SC, Rosenbaum HD. Gamma radiation in the treatment of squamous cell carcinoma of the limbus. Am J Ophthalmol 1976;55:811-815.
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No. 3
16. Philipp W, Daxecker F, Langmayr J, Gottinger W. Spontane ous corneal rupture after strontium irradiation of a conjuncti val squamous cell carcinoma. Ophthalmologica 1987; 195: 113-118. 17. Peksayar G, Soyturk MK, Demiryont M. Long-term results of cryotherapy on malignant epithelial tumors of the conjuncti va. Am J Ophthalmol 1989;15:337-340. 18. Ferry AP, Meltzen MA, Taub RN. Immunotherapy with dinitrochlorobenzene (DNCB) for recurrent squamous cell tumor of conjunctiva. Trans Am Ophthalmol Soc 1976; 74: 154-171. 19. Danopoulos ED, Danopoulos IE, Liarikos SB, Merkuris KM. Effects of urea treatment in malignancies of the conjunctiva and cornea. Ophthalmologica 1979;178:198-203. 20. Yeatts RP, Ford JG, Stanton CA, Reed JW. Topical 5fluorouracil in treating epithelial neoplasia of the conjunctiva and cornea. Ophthalmology 1995;102:1338-1344. 21. Wilson MW, Hungerford JL, George SM, Madreperla SA. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 1997;124:303-311. 22. Heigle TJ, Stulting RD, Palay DA. Treatment of recurrent conjunctival epithelial neoplasia with topical mitomycin C. Am J Ophthalmol 1997;124:397-399. 23. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 1991;98:314-321. 24- Parrish RK. Who should receive antimetabolites after filter ing surgery? Arch Ophthalmol 1992;110:1069-1071. 25. Finger PT, Milner MS, McCormick SA. Topical chemothera py for conjunctival melanoma. Br J Ophthalmol 1993;77: 751-753. 26. Frucht-Pery J, Pe'erJ. Use of mitomycin C in the treatment of conjunctival primary acquired melanosis with atypia. Arch Ophthalmol 1996;114:1261-1264. 27. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117:164-168.
EDITORIAL
383