Siganos, Charalambos S. M.D., Ph.D.; Kozobolis, Vassilios P. M.D., Ph.D.; Christodoulakis, Emmanuel V. M.D.
Purpose. To evaluate the efficacy of intraoperative mitomycin-C in excision of ocular surface neoplasia for prevention of recurrence.
Methods. Seven patients (eight eyes), three men and four women, aged 56 to 87 years (mean, 73.8 years), with lesions suspicious for corneal or conjunctival neoplasia, were operated on between October 1998 and March 2000. During excision of the lesion, mitomycin-C 0.02% was applied intraoperatively for 5 minutes. In two cases, excision was combined with conjunctival limbal autograft transplantation. All excised lesions were sent for histopathologic evaluation.
Results. During the follow-up period ranging from 6 to 28 months (mean, 16 months) one patient (one eye) died of an unrelated cause. Histopathologic study showed four cases of squamous cell carcinoma, one case of carcinoma in situ, two cases of dysplasia, and one case of actinic keratosis. Of the eight eyes, no clinical recurrence of the lesion occurred in seven eyes, whereas one eye with squamous cell carcinoma showed mild recurrence 5 months after surgery and was successfully treated with topical mitomycin-C. Up to the last follow-up of this case 10 months later, the lesion did not recur.
Conclusion. The excision of conjunctival and corneal epithelial neoplasia combined with the intraoperative use of mitomycin-C seems to reduce the recurrence rate. The combined use of mitomycin-C and conjunctival limbal autograft transplantation in two cases did not alter the surgical outcome. More cases and a longer follow-up are needed to establish the efficacy of such an approach.
The severity of epithelial neoplasia of the cornea and conjunctiva differs according to the degree of epithelial involvement and invasion, and the spectrum varies from actinic keratosis to variable degrees of dysplasia, to carcinoma in situ and to the more severe invasive squamous cell carcinoma. 1–3
The most widely accepted standard treatment of neoplastic conjunctival lesions includes surgical excision. In addition, several adjunctive intraoperative or postoperative treatments have been used to decrease the recurrence rate. Intraoperative treatments include extensive cryotherapy, 1,3–5,6 alcohol keratectomy, and lamellar sclerokeratectomy, 2 whereas postoperative ones include β-irradiation, 7,8 topical urea, 9 immunotherapy with dinitrochlorobenzene, 10 and more recently topical antimetabolites, such as mitomycin 11–15 and 5-fluorouracil, 16–19 which have also been used successfully as sole treatment (without surgical excision) for recurrent cases of noninvasive epithelial neoplasias.
Although to date there is no universally accepted treatment, most authors seem to agree that one of the most important factors that significantly decreases the recurrence rate is histologically proven complete tumor excision.
Limbal autograft transplantation, a procedure well established for the restoration of viable epithelium in ocular surface disorders, has also been used to promote epithelialization and prevent fibrovascular proliferation and conjunctivalization of the cornea, in combination with excision of large neoplastic lesions involving the limbus with possible limbal deficiency. 20–23
We introduce the use of intraoperative mitomycin-C as an adjunctive treatment to surgical excision for eight cases with variable degrees of ocular surface epithelial neoplasia. In two of these cases, because of large extension of the lesions, conjunctival limbal autograft transplantation was additionally performed.
PATIENTS AND METHODS
Seven patients (eight eyes), three men and four women, aged between 56 and 87 years (mean, 73.8 years), presented in our cornea service with conjunctival lesions. On examination, the clinical findings were consistent with conjunctival limbal carcinoma (four eyes) (Figs. 1 and 2), conjunctival leukoplakia (two eyes), conjunctival and corneal intraepithelial neoplasia (CCIN) (one eye) (Fig. 3), and pterygium (one eye). The lesions' size ranged from 4 × 4 mm (smallest) to 26 × 15 mm (largest). Schirmer test values with anesthetic in all patients ranged from 6 to 10 mm. The patients were operated on between October 1998 and March 2000 by one surgeon (C.S.S.).
Six eyes were operated on under local retrobulbar anesthesia, and two eyes under general anesthesia (Table 1). The lesions were excised with superficial keratectomy at the corneal side and superficial sclerectomy at the conjunctival side. An attempt was made to excise the lesions with a safety margin beyond the clinically evident extension; extension of the lesions was marked using a surgical marker at the beginning of surgery. After excision, mitomycin-C 0.02% soaked in microsponges was applied for 5 minutes (two microsponges for 2.5 minutes each) on the sclera at the area of the excised lesion and covered during application time through pulling of the remaining conjunctival tissue with two conjunctival forceps. Mitomycin-C was then washed away using profuse irrigation with 30 mL of balanced salt solution.
The remaining conjunctiva was then sutured to the sclera using three 10/0 nylon sutures, leaving approximately 2 or 3 mm of bare sclera between the suture site and limbus. In two cases (cases 1 and 7) with large lesions involving more than half the limbal diameter, after mitomycin application, conjunctival limbal autograft transplantation was performed using limbal tissue (three clock hours) and conjunctiva (enough tissue to cover the bare area) from the fellow eye. The conjunctival limbal graft was sutured using three 10/0 nylon interrupted sutures at the corneal side and five 10/0 nylon sutures at the scleral side. All excised lesions were sent for histopathologic evaluation.
Eyes were patched postoperatively with an antibiotic–steroid ointment, in addition to temporary tarsorrhaphy in two cases (cases 1 and 7) (Table 1) using one 4/0 silk mattress suture aiming at protection of the autograft and enhancement of epithelialization. All patients were instructed to use preservative-free artificial tears frequently and antibiotic–steroid (tobramycin–dexamethazone) eyedrops six times a day, tapered over a 3-month period. Tarsorrhaphy sutures were removed after epithelialization was completed.
The follow-up period ranged from 6 to 28 months (mean, 16 months). One patient (one eye) died of an unrelated cause 8 months after surgery (case 7) (Table 2).
In all eyes, corneal and conjunctival epithelialization time ranged from 5 to 25 days (mean, 14.1 days) (Table 2). No postoperative complications related to surgery, mitomycin-C, or postoperative medications were encountered.
Histopathologic examination showed four cases of squamous cell carcinoma, two cases of dysplasia, one case of carcinoma in situ, and one case of actinic keratosis. In three cases, the histopathology examination showed the presence of malignant tissue in depth and in the peripheral excised margins of the lesion (cases 1, 6, and 7) (Table 1). In the rest of the cases, the histopathologic report was indicative of complete tumor excision.
In seven of the eight eyes, no clinical recurrence occurred during the follow-up period. In one eye with squamous cell carcinoma (case 6), a small recurrent lesion measuring 2 × 3 mm and extending 1 mm onto the cornea resembling clinical CCIN, was discovered during follow-up 5 months after surgery (Fig. 2B). The lesion was treated with mitomycin-C 0.02% eyedrops four times a day for 2 weeks. The lesion decreased in size and eventually disappeared in 45 days. No recurrence was evident during the follow-up period (last examination 10 months after treatment with mitomycin-C) (Fig. 2C).
We studied the efficacy of intraoperative mitomycin-C as an adjuvant treatment to excision of ocular surface neoplasias, in an attempt to prevent recurrence. The recurrence rate of CCIN and conjunctival squamous cell carcinoma ranges from 15% to 52%. 1 Topical application of mitomycin-C eyedrops was reported to successfully treat most recurrent cases of CCIN in a multicenter study. 12 The safety, however, of the home use of mitomycin-C eyedrops is a controversial issue because it is related to various complications, such as mild pain, photophobia, and iritis, and the more severe corneal and scleral melting and perforation. 24–26 The application of mitomycin-C intraoperatively to prevent recurrence of primary and recurrent pterygia is well established in the literature. 27–30 We therefore think that the use of such treatment in conjunctival lesions with clinical suspicion of malignancy is justified.
We treated seven eyes of seven patients with clinical signs consistent with conjunctival and corneal neoplasia and one eye with a clinical picture of pterygium, which was the fellow eye of histopathologically proven neoplasia of one of the seven patients.
An attempt was made in all cases to completely excise the conjunctival lesions, which is probably the most important factor in recurrence prevention.
All patients had acceptable Schirmer test values before surgery. Mitomycin-C in a concentration of 0.02% was applied on the area of the excised lesion for 5 minutes and then washed with 30 mL of balanced salt solution. This concentration and application time was reported to be fairly safe in the literature. 27–30 No postoperative toxicity complications related to mitomycin-C were encountered in our patients.
In two eyes with large conjunctival carcinomas covering more than half the limbal diameter, in addition to excision and mitomycin-C, conjunctival limbal autograft transplantation from the fellow eye was performed. The use of mitomycin in these cases did not seem to influence the graft viability or the rate of epithelialization.
The epithelialization time ranged from 5 to 25 days. Epithelialization time was proportional to the size of the excised lesions (Table 2). Indeed, the longest time (20, 23, and 25 days) was observed in three cases of large carcinomas (cases 7, 6, and 1), in two of which surgery was combined with conjunctival limbal autograft, whereas in the rest of the cases, the mean epithelialization time was 9 days (range, 5–13 days). No postoperative complications were found in the fellow eyes of the two cases that underwent conjunctival limbal autograft transplantation, and epithelialization of the cornea in these eyes occurred within 5 days.
The postoperative follow-up period ranged from 6 months to 28 months. In the four eyes with noninvasive neoplasia, the follow-up period ranged from 10 to 18 months (mean, 14 months). During this period, no clinical recurrence was observed in any of these cases (Table 2). In the four eyes with squamous cell carcinoma, the follow-up period ranged from 6 to 28 months (mean, 18 months). During this period, no clinical recurrence occurred in three eyes, although in one eye, mild recurrence clinically resembling CCIN was observed 5 months after surgery and was successfully treated with mitomycin-C 0.02% eyedrops four times a day for 2 weeks. The recurrent lesion disappeared in 45 days and did not recur up to the last follow-up examination 10 months after treatment (Fig. 2C). The histopathologic report in this case showed malignant cell infiltration at the excised margins. This might explain the recurrence, which was in fact situated at the periphery of the excised area (Fig. 2B). Conversely, the report on another two eyes with squamous cell carcinoma also showed malignant infiltration in depth and in the margins. Malignancy has not yet recurred in these eyes, perhaps because mitomycin applied on the bare area and covered by the pulled remaining conjunctiva might have exerted its cytotoxic activity to the remaining not clinically visible malignant tissue.
Although there is a considerable follow-up time, the possibility of recurrence cannot be excluded. There are data in the literature indicating recurrence after as long as 15 years. 31 We must point out that “no recurrence” in our cases was not proved histologically. Nevertheless, the clinical picture to date does not suggest that biopsy is necessary. Finally, as in most of the prospective studies dealing with conjunctival neoplasias, the number of cases is limited and cannot prove or disprove the efficacy of such treatment. The outcome of this work can be encouraging for further studies and more cases to compare the results with other types of treatment.
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