Abstract
Purpose
The aim of the study was to demonstrate the clinical outcomes after resection of conjunctival melanoma (CM) followed by topical interferon (IFN) alpha 2b after a long follow-up.
Methods
Two consecutive CM patients were treated using tumor excision followed by topical IFN alpha 2b (1,000,000 UI/mL) four times a day for 12 weeks. The second case presented positivity due to the presence of tumor cells in the lower margin of the resection. TNM staging was T1c, N0b, M0, and T1b in the first case and T1b, N0b, M0 in the second case. Follow-up was 72 and 71 months, respectively.
Results
No side effects were observable after the administration of topical IFN alpha 2b. After extensive evaluation and imaging with computed tomography, no regrowth or distant metastasis was noticed during the follow-up period in both cases.
Conclusions
IFN alpha 2b could be used as a co-adjuvant treatment after CM resection, in an attempt to reduce the possibility of recurrences.
Keywords: Conjunctival melanoma, Primary acquired melanosis, Interferon alpha 2b, Ocular surface tumors
Introduction
Surgery is the first choice of treatment for conjunctival melanoma (CM). Excision with wide margins and double freeze-thaw cryotherapy is the preferred treatment [1]. However, no standard topical adjuvant therapy has yet been established. Primary acquired melanosis (PAM) with atypia can turn into CM which can induce local relapse after resection and regional or systemic metastasis. CM may require local brachytherapy to prevent recurrences but cannot eliminate presumable micrometastatic disease prior to surgery. Brachytherapy is applied once the conjunctiva is already healed. Other centers prefer to use adjuvant therapies without sacrificing conjunctiva. Topical interferon (IFN) alpha 2b recurrence may be an alternative. IFN alpha 2b has been used successfully as primary or adjuvant treatment of ocular surface squamous neoplasia [2]. Topical IFN alpha 2b has been used also in isolated cases of conjunctival PAM with good successful rates and tolerance [3, 4, 5, 6, 7]. Clinical evidence of the utility of IFN alpha 2b in the CM context is limited [8]. Several reports have described favorable outcomes in some but not all cases [3, 6, 9, 10, 11]. The drug may be useful if the margins remain affected after surgery in patients with PAM evidencing atypia or melanoma in situ [3, 4, 6, 10]. However, tumor regrowth or metastasis may develop despite topical drug application. The aim of this study is to demonstrate the clinical outcomes after resection of CM followed by topical IFN alpha 2b after a long follow-up.
Case Series
A retrospective study with two consecutive CM patients was performed.
Case 1
A 66-year-old male referred to our hospital due to the increase in size of a bilobed pigmented lesion in the temporal bulbar conjunctiva with corneal invasion in the right eye (Fig. 1). The inferior part of the lesion measured 6 × 5.5 mm and the superior with corneal invasion 5 × 5 mm approximately. He underwent excisional biopsy.
Fig. 1.
CMs of the 2 cases. Initial (stage T: CM of the bulbar conjunctiva). Case 1: T1c (more than 2, less than/equal 3 quadrants). Case 2: T1b (more than 1, less than/equal 2 quadrants'), amniotic membrane glued to the resection site with fibrin glue prior topical IFN alpha 2b treatment (center) and later photographs.
Case 2
A 68-year-old female presented to our hospital due to an increase in a pigmented lesion in the temporal conjunctiva of the right eye (Fig. 1). The lesion invaded the cornea and measured 7 × 8 mm approximately. She underwent excisional biopsy. Both were treated with surgical resection using the “no-touch technique” [1] followed by topical IFN alpha 2b (1,000,000 UI/mL) four times a day as primary treatment.
Conjunctival resection was performed with margins of 4 mm outside to the visible tumoral lesion. To resect the corneal invasion area, 70% alcohol was applied to the tumor margins in order to perform an epitheliectomy and removal of the tumor mass. Subsequently, cryotherapy was applied to the conjunctival edges of the resection. The scleral bed was covered with an amniotic membrane placed below the conjunctival rim of the border of the resection. The amniotic membrane was glued with fibrin glue (GFG).
The second case had a positive inferior margin in the excised apparent healthy conjunctiva. Topical IFN was used to prevent recurrences after resection and avoid brachytherapy. IFN alpha 2b was started to apply 1 week after resection. The reason was to wait for the histological result and the preparation of the IFN eye drops in our hospital pharmacy after having informed the patients and having obtained written consent for the use of this medication.
After conjunctival resection, malignant cells may remain in depth or in the resection margins and cause a new melanoma later. The duration of topical treatment with IFN alpha 2b was 12 weeks. Figure 1 shows the clinical presentations, and Table 1 shows the clinical characteristics and treatments. Photobiomicroscopic follow-up was performed every 2 weeks during topical treatment and every 6 months thereafter. Computed tomography (cranial, orbit, thorax, and abdomen) and blood tests were performed every 6 months. All patients were fully informed and gave written signed consent for surgical and topical chemotherapeutic treatment and possible publication of any accompanying images. This study was conducted in accordance with all relevant ethical standards of the Declaration of Helsinki. The written consent of this adjuvant therapy after informing them of the possible side effects both topical and systemic was obtained. The application to institutional review board could be waived because this study is based on case series with noninvasive methods. Table 1 and Figure 1 summarize the outcomes and follow-up of both cases. No local side effects and systemic as flu-like symptoms with IFN alpha 2b were observed. No tumor regrowth and distant metastasis were noticeable during the follow-up of 72 and 71 months of follow-up, respectively.
Table 1.
Clinical characteristics, treatments, and outcomes in 2 cases of CM
| Case | 1 | 2 |
|---|---|---|
| Age, years | 66 | 68 |
| Sex | Male | Female |
| Tumor origin | De novo | PAM (6 years known) |
| TNM staging (AJCC 7th) | T1c, N0b, M0 | T1b, N0b, M0 |
| Surgery | No-touch technique | No-touch technique |
| OS reconstruction | Amniotic membrane (GFG) | Amniotic membrane (GFG) |
| Histology | Conjunctival melanoma CMIN >5 | Conjunctival melanoma CMIN >5 |
| Affected surgical margins | No | Yes (inferior edge) |
| Topical adjunctive treatment | IFN alpha 2b (1,000,000 UI) | IFN alpha 2b (1,000,000 UI) |
| 4 times a day | 4 times a day | |
| Topical IFN duration, weeks | 12 | 12 |
| Adverse effects | No | No |
| Follow-up, months | 72 | 71 |
| Regrowth | No | No |
| Distant metastasis | No | No |
PAM, primary acquired melanosis; AJCC 8th, TNM staging according to the 8th American Joint Committee on Cancer Classification for conjunctival melanoma; OS, ocular surface; GFG, glued with fibrin glue; IFN, interferon; UI, international units.
Discussion
IFN alpha 2b constitutes an immunomodulator glycoprotein with direct effect on tumor cells. IFN may act on the tumor by means of activation of the host immune system. It is difficult to evaluate the utility of topical IFN alpha 2b after CM resection given the rarity of the condition (0.24–0.8 cases/million subjects) [8] and the short-term follow-up (under 5 years) of most patients [3, 4, 6, 9, 10, 11] (Table 2). Finger et al. [3] were the first in demonstrating the regression of 4 cases of CM after topical IFN alpha 2b during 3 months. Posteriorly, Kase et al. [9] reported 2 cases of CM treated after tumor resection with additive topical IFN alpha 2b over a 6-month period with follow-up of 24 months. Complete tumor resolution was achieved in 80% of cases with involved margins described in three reports; 20% did not respond [3, 4, 10]. However, a recent study about 5 cases described complete resolution in only 40% of patients (stage T1 and underwent 54 and 33 months of follow-up); 40% developed recurrences, and 20% did not respond at all [11]. Also, patients of stages T2 and T3 responded well in previous reports, but the longest follow-up was 17 months [4]. Recurrence was reported in a case with follow-up of 62 months [6]. It is not clear whether the resection margins were affected in this case. Another study included two favorable cases (one each of stage T2 and T3) with follow-up of 78 and 46 months [10]. We observed no local recurrence or distant metastasis during 6 years of follow-up in stage T1 patients with or without affected surgical margins. Previous studies have indicated that IFN alpha 2b may be useful in stage T1 cases with affected margins [4, 10, 11]. Indeed, the drug may be very useful even if the margins are histologically tumor-free. Some edge of the apparently healthy conjunctiva may be infiltrated by remanent cells after the surgical excision that could trigger a regrowth or metastasis. Faced with these possible situations, topical treatment with IFN alpha 2b can be very useful, helping to eliminate these remaining cells. Cases describing distant metastases [6, 10, 11] must be interpreted carefully; the metastases may have originated prior to surgery, becoming obvious only later. Isolated cases of CM in stage T1b treated using the “no-touch technique” without associating any topical therapy have been reported without regrowth or distant metastases [12]. However, the follow-up was only 16 months. Our short cases report featured longer follow-up than most previous studies [3, 4, 9, 11], being only slightly less than the 77-month and 78-month follow-ups of an earlier study [10]. Apart from our 2 cases, only 3 patients treated via the regimen that we employed have been followed up for more than 5 years [10]. The detailed mechanism of action of IFN alpha 2b in the CM context remains unclear [8]. The frequency and duration of administration of IFN alpha 2b drops are empirical because no data from large studies are available. All published reports use an empirical frequency of administration consisting of one drop 4 times a day with duration since 1.5–10 months [3, 4, 6, 9, 10, 11]. The mean therapy duration of patients with PAM or CM treated with IFN alpha 2b in the most large reported series was 14.4 weeks [6]. We treated during 12 weeks based on the reported average duration in previous publications for ocular surface squamous neoplasia treatment [2] and experience in diffuse PAM treatment with IFN alpha 2b [7]. More recently, in a multicenter study on 288 cases of MC, IFN alpha 2b was used as an adjuvant in 20 cases (6.9%) [13]. This study concludes that AJCCT staging can be used to predict local tumor recurrence after treatment more than the administration of adjuvant therapy such as cryotherapy, brachytherapy, or topical chemotherapy. However, the report does not clearly specify the specific TNM stage of the cases treated with adjuvant IFN alpha 2b. On the other hand in the literature, there are no comparative studies of cases operated by simple excision and cases treated by excision plus adjuvant therapy with topical IFN alpha 2b.
Table 2.
Reported CM treated with topical IFN alpha 2b and outcomes
| Report | Cases, n | Treatment duration, months | Follow-up, months | Metastases | Complete remission |
|---|---|---|---|---|---|
| Finger et al. [3] | 5 | 3 | 11–20 | None | 4/5 |
| Herold and Hintschich [4] | 5 | 1.5–4.5 | 15–27 | None | 5/5 |
| Kase et al. [9] | 2 | 6 | 24 | None | 2/2 |
| Garip et al. [6] | 7 | 1.5–4.5 | 8–62 | 1/7 | 3/7* |
| Kikuchi et al. [10] | 5 | 6–10 | 18–78 | 1/5 | 4/5 |
| Benage et al. [11] | 5 | 3–6 | 12–54 | 1/5 | 2/5** |
Insufficient documentation and loss in retrospective data were reported on 4 cases.
Recurrence was noted in 2 cases, one being exitus. No response in 1 case led to ultimate enucleation after 3 months of IFN alpha 2b topical treatment.
Topical IFN alpha 2b is an off-label administration not commercially available. The stability and preservation of the principal active form after it is prepared for instillation have not been reported [14]. This could be a cause that in some series the percentage of success was lower. Because it is a long treatment, the patient's compliance must also be taken into account.
Our observations support that adjunctive IFN alpha 2b may contribute the survival to 6 years after resection in stage T1 in patients with or without affected margins, and we corroborate previous studies (3, 6, 9–10). IFN alpha 2b may be maintained as an adjunctive therapy after resection of a CM due to its good tolerance and efficacy in preventing recurrences.
Statement of Ethics
Written informed consent was obtained from participants for publication of the details of their medical case and any accompanying images. No IRB was necessary as a research study was not conducted.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None to declare for this manuscript.
Author Contributions
Huerva V. is responsible for acquisition of clinical cases and data, preparation of the manuscript and criticism with the data, and final approval. Cid-Bertomeu P. is responsible for acquisition of clinical and interpretation data, and criticism with the data and final approval. Espinet R. is responsible for acquisition of clinical information and data, the interpretation of the data, analysis of the data, and final approval. Canto L.M. is responsible for the acquisition of the cases and the data and preparation of the manuscript, and final approval.
Data Availabilty Statement
All data generated or analyzed in the study have been referenced in the manuscript. Further inquiries can be directed to the corresponding author.
Acknowledgment
The authors would like to thank Dr. Vilardell of the Department of Pathology, Arnau University Hospital of Vilanova from Lleida, for the histological study of cases.
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