Liquid nitrogen cryotherapy for primary pterygia may prevent recurrence

Thomas John

Pterygium is a fairly common ocular surface lesion, especially in the global sun belt regions. As such, many ophthalmologists are engaged in the surgical management of pterygia for symptomatic or cosmetic reasons. While the exact etiology of pterygium is not fully understood, cell apoptosis and proliferation are known to play a significant role in its pathogenesis.

There is no consensus on an optimal treatment after pterygium excision that will result in a good postoperative outcome without the risk of possible recurrence, and recurrent pterygium is often worse than the primary lesion. Numerous surgical techniques with varying recurrence rates have been described in the literature. An ideal surgical treatment should utilize a relatively simple surgical technique that can be duplicated easily, provide a cosmetically acceptable postoperative appearance with a relatively quiet eye, and entail no recurrences of the pterygium following surgical excision. In the absence of such an ideal technique, surgeons are seeking a procedure that offers the least degree of recurrence after excision.

In this column, Dr. Fraunfelder describes a surgical technique to treat pterygium that uses liquid nitrogen cryotherapy and does not employ conjunctival autograft or amniotic membrane transplantation. He recommends performing this technique for primary pterygia while avoiding it for recurrent pterygia. While the procedure appears promising for primary pterygia, longer follow-up and continued monitoring for any recurrence are warranted.

Thomas John, MD
OSN Surgical Maneuvers Editor

by Frederick W. Fraunfelder, MD

Pterygia can present with symptoms of eye redness, foreign body sensation, tearing, photophobia and/or ocular pain. Some patients have visual loss due to induced astigmatism or encroachment of pterygia onto the visual axis. Clinically, pterygia look like wing-shaped folds of conjunctival and fibrovascular tissue extending over the limbus and encroaching onto the superficial cornea.

These benign proliferations are thought to arise from activated and proliferating limbal epithelial stem cells. The pathogenesis of pterygia is unknown, but epidemiologic studies have implicated ultraviolet light, exposure to the environment and chronic irritation as causative factors. These external factors may disrupt the signals to epithelial stem cells for apoptosis or proliferation. In essence, it is hypothesized that there may be a disruption in normal conjunctival cellular homeostasis.

Surgical technique

If a pterygium places a patient at risk for vision loss or is causing symptoms unacceptable to the patient, an excisional biopsy with adjuvant liquid nitrogen cryotherapy can be performed. The avulsion technique can be used to remove the pterygium, as described by multiple authors.

In a published series on this surgical technique, all subjects were outpatients who had local anesthesia with a combination of a single drop of topical proparacaine and subconjunctival injection of 0.5 cc to 1 cc of 1% lidocaine with epinephrine around the base of the pterygium. The conjunctival portion of the pterygium was first dissected forward to the corneoscleral limbus, and a 4-0 silk suture was tied around the base of the pterygium at the limbus. The pterygium was then avulsed by pulling on the suture in the direction of the cornea.

Cryotherapy, with a 2 mm cryoprobe attached to a Brymill Cryogenic Systems unit, was then performed, with the tip of the cryoprobe in contact with the corneoscleral limbus for approximately 1 second. A double freeze-thaw technique was used, with approximately 30 seconds elapsing between freeze applications. After the cryotherapy, the conjunctiva was closed up to the limbus with 6-0 plain gut sutures. Histopathological results revealed elastotic degeneration of collagen and the appearance of subepithelial fibrovascular tissue. Malignancy was ruled out with pathologic examination. Patients were prescribed topical ocular steroids and topical ofloxacin to be taken four times daily for 2 weeks and were instructed to return for follow-up visits at 1 day, 1 week, 2 weeks, 3 months, 6 months and yearly thereafter.

Pterygium involving the bulbar conjunctiva and cornea of the right eye (Patient 6, Table 1).

Patient with pterygium treated with excision and cryotherapy (Patient 6, Table 1).

Patient with a pterygium (Patient 6, Table 2).

Resolution of pterygium after excision and cryotherapy. Images: Fraunfelder FW

Methods, results

Two groups of patients underwent liquid nitrogen cryotherapy in this published case series: patients referred to Casey Eye Institute who had no prior surgery and patients in whom pterygia had recurred after excision at another hospital without adjunctive therapy. Eighteen patients who had no prior surgery had a median follow-up of 24.5 ± 15 months (range: 10 to 56 months). The median age was 56 ± 12 years (range: 36 to 74 years), with 11 men and seven women. Only one patient in this group had a recurrent pterygium, which recurred at 9 months after surgery (Table 1), for a recurrence rate of 5.5%.

In the group of six patients presenting with recurrent pterygia, the median age was 39 ± 14 years (range: 31 to 67 years), with three men and three women and a median follow-up of 27 ± 26 months (range: 13 to 80 months) (Table 2). Four patients had recurrent pterygia, at an average of 13 ± 19 months (range: 2.5 to 42 months) after excision and cryotherapy. Four patients were Hispanic, and three of these four patients had a recurrence at an average of 3.3 ± 1 month (range: 2.5 to 4.5 months) after excision and cryotherapy.

Mechanism of action

In epithelial cells, normal tissue homeostasis is maintained by a tight coordination between cellular apoptosis and cellular proliferation. In published reports, pterygium specimens display an abnormal number of apoptotic cells when compared with normal bulbar conjunctival tissue. The specimens also display an abnormal expression of genes associated with the control of apoptosis, including P53, BAX and BCL2. Pterygia may arise as a result of incorrect control of cellular apoptosis rather than from an increase in proliferative capacity.

Liquid nitrogen cryotherapy after pterygium excision may work by direct cytotoxicity and by inducing apoptosis in proliferating epithelial stem cells. The cryogen may also be effective in eradicating the microvasculature of pterygia because these tumors are highly vascularized. Prior research has shown liquid nitrogen cryotherapy to be effective in eradicating conjunctival vascular tumors.

Recurrence rates

The 5.5% recurrence rate in the case series of 18 patients compares favorably with the recurrence rates of various adjunctive therapies reported in the literature. For instance, Donaldson and Alfonso report a recurrence rate of 6% with conjunctival autograft, 13% with beta-irradiation, 29% with mitomycin C, and 53% with excision alone after more than 5 years of follow-up. Küçükerdönmez and colleagues report a recurrence rate of 10% with conjunctival autograft and 21% with amniotic membrane graft after pterygium excision with more than 1 year of follow-up. Luanratanakorn and colleagues report a recurrence rate of 13% with conjunctival autograft and 28% with amniotic membrane transplantation after 6 months of follow-up.

Mikaniki and Rasolinejad compared MMC 0.02% eye drop application for 4 days after pterygium excision to excision alone without adjunctive therapy in over 400 patients. At 1 year, there was a 20% recurrence rate for excision alone and a 30% recurrence rate after 5 years. In the group treated with MMC, there was a 1% recurrence rate at 1 year and 5 years.

Bekibele and colleagues studied 5-FU adjuvant treatment after excision compared to excision with conjunctival autograft with less than 1 year of follow-up. The recurrence rate was 11% with intraoperative 5-FU application and 12% with conjunctival autograft.

Katircioðlu and colleagues compared amniotic membrane graft, conjunctival autograft and autograft combined with MMC with approximately 1 year of follow-up. The recurrence rate was 16% for amniotic membrane graft, 25% for autografts, and there were no recurrences in eight eyes after combination MMC and autograft.

In the liquid nitrogen case series, the absence of recurrence in the majority of patients with a median follow-up of 24.5 months is strong evidence that cryotherapy is an effective adjunctive therapy. Because most pterygia recur within the first year after treatment, absence of recurrence beyond 1 year may mean that cryotherapy can be curative for this surface eye disease.

In the recurrent pterygia treated with liquid nitrogen cryotherapy as adjunctive therapy after excision, the recurrence rate was 66%. Moreover, the recurrence occurred very rapidly in the Hispanic patients (Table 2). The recurrences may be related to the inadequacy of cryotherapy for recurrent pterygia and possibly surgeon technique in removal of the primary pterygium. Nevertheless, liquid nitrogen cryotherapy is not recommended for recurrent pterygium based on the small case series published so far.

References:

• Coroneo MT, Di Girolamo N, Wakefield D. The pathogenesis of pterygia. Curr Opin Ophthalmol. 1999;10(4):282-288.
• Fraunfelder FW. Cryotherapy for pterygia. Ophthalmology. 2008;115(12):2314-2314.
• Fraunfelder FW, Fraunfelder FT. Liquid nitrogen cryotherapy of a conjunctival vascular tumor. Cornea. 2005;24(1):116-117.
• Gebhardt M, Mentlein R, Schaudig U, et al. Differential expression of vascular endothelial growth factor implies the limbal origin of pterygia. Ophthalmology. 2005;112(6):1023-1030.
• Liang K, Jlang Z, Ding BQ, Cheng P, Huang DK, Tao LM. Expression of cell proliferation and apoptosis biomarkers in pterygia and normal conjunctiva. Mol Vis. 2011;17:1687-1693.
• Sakoonwatanyoo P, Tan D, Smith DR. Expression of p63 in pterygium and normal conjunctiva. Cornea. 2004;23(1):67-70.
• Wang IJ, Hu FR, Chen PJ, Lin CT. Mechanism of abnormal elastin gene expression in the pinguecular part of pterygia. Am J Pathol. 2000;157(4):1269-1276.

• Frederick W. Fraunfelder, MD, is the director of cornea and refractive surgery and the Martha and Eddie Petersen endowed professor of oph-thalmology at the Casey Eye Institute. He can be reached at Casey Eye Institute, 3375 SW Terwilliger Blvd., Portland, OR 97239-4197; 503-494-4318; fax: 503-418-2284; email: eyedrug@ohsu.edu.
• Edited by Thomas John, MD, a clinical associate professor at Loyola University at Chicago and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. He can be reached at 708-429-2223; fax: 708-429-2226; email: tjcornea@gmail.com.
• Disclosures: Dr. Fraunfelder’s research was supported in part by an unrestricted grant to Casey Eye Institute from Research to Prevent Blindness. Dr. John has no relevant financial disclosures.