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Clinical Sciences

Combined Surgery, Cryotherapy, and Mitomycin-C for Recurrent Ocular Surface Squamous Neoplasia

Khokhar, Sudarshan M.D.; Soni, Ambarish M.D.; SinghSethi, Harinder M.D.; Sudan, Rajeev M.D.; Sony, Parul M.D.; Pangtey, Mayank S. M.D.

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Ocular surface squamous neoplasia includes dysplasia, carcinoma in situ, invasive squamous cell carcinoma, and actinic keratosis. 1 Most of these lesions are slow-growing, localized tumors with similar clinical appearance. 1,2

The management of these ocular surface squamous neoplasias includes simple surgical excision, surgical excision with wide margins, 3 surgical excision with cryotherapy to the base and involved limbus, 4 and Mitomycin C (MMC) therapy. 5

Postoperative treatments have included supplemental radiotherapy, 6 dinitrochlorobenzene, 7 urea, 8 Mitomycin C, 5 interferon, 9 and 5-fluorouracil. 10 All these approaches have been effective in the reducing recurrence rate, albeit with definite ocular side effects.

Faced with a burgeoning referral base of patients with recurrent ocular surface squamous cell neoplasms who were not likely to present for regular follow-up care, we were tempted to combine an admittedly aggressive mixture of surgical excision with wide margins, cryotherapy, and MMC application to effectively eradicate the recurrent lesions.


Five eyes of five patients with recurrent lesions that were clinically diagnosed as ocular surface squamous neoplasia were selected for combined modality therapy. All patients had been treated outside (other than our center), had one or more recurrences, and had been referred to our center for treatment.

Each patient had complete history and systemic and ocular examination including photography, mapping of extent of involvement, clinical appearance of lesion, and a search for any systemic spread. Fluorescein staining of the lesion was done to determine the extent of corneal involvement. Patients were assigned to surgery by one surgeon (S.K.) and similar protocol was followed in all patients.

Surgical Procedure

First, a wide excision with a 2- to 3-mm margin of the conjunctival lesion was done. The bleeders were cauterized with bipolar cautery. Scar tissue was cleaned from bare sclera using crescent blade until apparently normal sclera appeared.

A superficial keratectomy of the corneal extension was done using the crescent blade. A margin of approximately 1 mm of normal-appearing corneal tissue was taken. The corneal extent was determined from the fluorescein staining at the edges of the visible lesion. Specimens were sent for histopathologic examination.

On the conjunctival side, the cut edge was lifted up from the sclera, and cryotherapy was applied in a triple rapid freeze slow thaw technique. The already frozen cryo tip was applied for 3 seconds to the required area and allowed to thaw slowly. After the probe had come off by itself, it was removed from the eye. The probe was refrozen and applied again. This procedure was repeated for a total of three applications. Cryotherapy was applied to the limbal margin in the same manner. After cryotherapy, 0.02 mg/mL MMC was soaked on Merocel sponge pegs. These pegs were placed on the bare sclera and then covered with conjunctival cut ends using a serrated forceps. The MMC was left in place for 5 minutes. After 5 minutes, the pegs were taken out and the whole operating field was extensively washed by copious amounts of normal saline. The sclera was left bare.

The eye was patched. Postoperatively, a topical antibiotic, steroid, and artificial tears were applied. Follow-up was done on postoperative days 1, 7, and 15 and then every month thereafter. A follow-up fluorescein staining was done to look for any epithelial defect and then later on to look for any early signs of recurrence.


All the patients were men ranging from 40 to 60 years of age. Of the five patients, four had one recurrence and one had a second recurrence after surgery. For all patients, all previous procedures had been done outside our center. Two of these patients had histologic reports of invasive squamous cell carcinoma, whereas other samples had not been sent for histopathology. Three of the patients had undergone excision with the primary diagnosis of pterygium. All five had their lesion on the nasal side involving both the conjunctiva and cornea (Table 1).

Patient demographics and summary of clinical data

The specimen sent after surgical resection of the lesion for histopathology showed that four patients had invasive squamous cell carcinoma and one had squamous dysplasia. We have followed up all five patients for 12 to 14 months. There have been no recurrences to date in any of them. One patient had a persistent epithelial defect that healed with patching after 2 weeks. The rest of the patients had complete epithelialization in 1 week.

We did not note any thinning of sclera, scleral necrosis, and uveitis in any of our cases.


Squamous cell carcinoma is a slow-growing tumor involving the conjunctiva, cornea, or both with little tendency to metastasize. 1 Nonetheless, both intraocular and distant metastases have been documented. 11–13 Thus, it is important to treat the tumor adequately and not just for cosmetic reasons. Recurrences are the bane of therapy for most modalities of treatment of squamous cell neoplasia. 1

Long-standing squamous dysplasia and carcinoma in situ can become invasive by breaching the underlying basement membrane. This invasion occurs more often on the conjunctival side than on the corneal side of the lesion, where Bowman's layer is relatively resistant to such invasion. 14

Simple excision with wide margins has been reported in one study to have a recurrence rate of 56% for incompletely excised tumors and 33% for those completely. 15

Combining cryotherapy with excision led to a lower recurrence rate of only 9%, all of which occurred within the first 2 years. 16 At the same time, the recurrence rate for the recurring tumor was higher (50%) compared with that of the primary tumor 28.5%. 17

We are additionally faced with a burgeoning patient load that comes from far away but who are loathe to seek follow-up care for economical or other reasons. Eradication of a greater number of cells seemed to us to be a logical solution to treat such patients who might not present for regular follow-up care.

Mitomycin C is a very potent alkylating agent and has been reported for treating lesions such as recurrent pterygium. 18 Intraoperative applications have been reported to be useful for the treatment of recurrent pterygium. 19 We surmised that this antimitotic effect of MMC coupled with the destructive effect of cryotherapy with triple freeze/thaw would be an effective therapy for recurrent lesions of ocular surface squamous neoplasia.

We did consider the possible untoward effects of cryotherapy 1 and MMC 20 and explained the possible risk to our patients. The results so far have been extremely gratifying, with no serious functional or anatomic complications.

We do not advocate this treatment for all patients because our series is too small to warrant such radical conclusions. Furthermore, the risks, although we did not have any, are possibly greater compared with more conservative therapies. These preliminary results, however, do suggest that a subset of patients with recurrent lesions may benefit immensely from this one-time procedure.


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Ocular surface; Squamous neoplasia; Mitomycin C; Cryotherapy; Surgical excision; Recurrence; Recurrent pterygium

© 2002 Lippincott Williams & Wilkins, Inc.