Cryotherapy after Topical Interferon Alpha 2b to Treat Conjunctival Primary Acquired Melanosis

Conjunctival primary acquired melanosis (PAM) develops gradually in middle age; a localized, patchy, flat multifocal, or diffuse lesion can give rise to a conjunctival melanoma (CM) [1]. Excision via double freeze-thaw cryotherapy is an elective treatment for cases with atypia in cases where the bulbar conjunctiva is involved [1]. Depending on the extent of the PAM, the direct closure of the conjunctiva may be insufficient for the reconstruction of the ocular surface. In these situations, the scleral bed can be covered with amniotic membrane placed below the conjunctival rim [2]. However, if the PAM with atypia affects the tarsal conjunctiva, it will be necessary to perform a radical surgery that can be mutilating, requiring reconstructive surgery of the eyelid. On the other hand, diffuse lesions may be sensitive to topical chemotherapy, and therefore an excision could not be required. Mitomycin C (MMC) was first used in the treatment of CM [3, 4]. The fact that MMC does not cross the basement membrane, the high percentage of recurrences, and high toxicity in the ocular surface has given way to other drugs such as the use of interferon alpha 2b (IFN-α2b) [3, 5]. Some reports show that topical IFN-α2b may be resolute in cases of PAM with atypia [6]. The inconvenience for the compliance with this treatment is the duration between 3 and 9 months [6]. Also, supplementary cryotherapy has been used to treat the conjunctival tumors [1]. We present a case of PAM affecting the bulbar conjunctival, fornix, and tarsal conjunctiva treated without the need for mutilating surgery.

A 64-year-old Caucasian female presented with diffuse pigmentation of the right eye involving the inferior tarsal conjunctiva, fornix, and inferotemporal bulbar conjunctiva (Fig. 1a). She was sent to us with the diagnosis of PAM to assess possible therapy. Given the extent of the lesion and its location, a wide mutilating excision was ruled out. After informing her of the possibilities of treatment, topical IFN-α2b treatment (1,000,000 IU/mL, 4 times a day) was commenced. This was well-tolerated; however, after 10 weeks, lesional regression was very slow (Fig. 1b). At this time, a new anatomopathological diagnosis was made. We performed three map biopsies in the areas of greatest pigmentation at the level of the fornix and the histological study showed a PAM with atypia (C-MIN 5) (Fig. 1c). Given the slow response and as a measure to avoid mutilating surgery, a local cryotherapy was proposed and we decided to apply a double freeze-thaw technique of cryotherapy (8 s at −80°C per application) to the entire pigmented lesion and topical IFN-α2b was ceased. This afforded progressive depigmentation, which was completed 2 months later (Fig. 1d). No recurrence of the lesion has been noted during 3 years of follow-up. This case corresponds in the histological study with C-MIN 5 (in situ neoplasm without invading the basal membrane). In this situation, the possibility of recurrence is lower. The patient continues monitoring through biomicroscopic observations every 6 months.

The patient was fully informed and gave written signed consent for topical chemotherapeutic treatment or cryotherapy and the possible side effects and possible publication of any accompanying images. This study was conducted in accordance with all relevant ethical standards of the Declaration of Helsinki. The application to Institutional Review Board could be waived because this study is based on a case report with noninvasive methods. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529667).

IFN-α2b has proven useful after surgery in cases with positive margins and in patients with PAM with atypia or melanoma in situ [6]; however, tumor regrowth or metastasis may develop despite topical IFN application [6]. No consensus has emerged on the optimal therapeutic approach for pigmented conjunctival lesions, especially PAM and CM, and the role of topical chemotherapy remains controversial. The timing of treatment cessation is controversial. Pigmentation can disappear even after treatment ceases [5]. MMC was used prior to the availability of IFN-α2b; the latter can serve as an alternative adjuvant therapy when MMC is poorly tolerated. Cryotherapy has been used as a supplementary treatment for conjunctival tumors [1]. The effect of cold produces denaturation of the basement membranes, which leads to the destruction of tumor cells. Usefully, this eliminates subclinical tumor cells and thus prevents recurrence. If cryotherapy kills all malignant cells, radical surgery may be avoided [1]. However, the possible adverse effects of excessive freezing include scleral and corneal thinning, cataracts, retinal scarring, and phthisis bulbi. Primary cryotherapy was used to treat only 1% of a long series of PAM patients [7] and topical IFN-α2b was successfully used to treat PAM associated with lentigo maligna of the eyelid [8]. Later treatment featured with application of cryotherapy and imiquimod 5% on the eyelid skin. In our present case, the slow elimination of pigmented tumoral cells could start on the application of topical IFN-α2b, but accelerated when cryotherapy was added; this denatures cell membranes and may thus aid conjunctival pigmentation eradication.

We suggest that a combination of topical IFN-α2b and cryotherapy can usefully eradicate an extensive PAM when eyelid surgery would be mutilating. The combination of the two procedures reduces IFN-α2b eyedrop administration time, enhancing patient compliance. The combination eradicated the conjunctival pigmentation without compromising ocular cosmesis.

The authors would like to thank Dr Jordi Soldevila for the presentation of the case.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

None to declare for this manuscript.

Valentín Huerva: is responsible for acquisition of clinical case and data, preparation of the manuscript, and criticism with the data and final approval. Felip Vilardel: is responsible of the histological study, criticism and final approval, Pau Cid-Bertomeu: is responsible for acquisition of clinical and, interpretation data, and criticism with the data and final approval.

All data generated or analyzed in the study have been referenced in the manuscript. Further inquiries can be directed to the corresponding author.