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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 36  |  Issue : 1  |  Page : 4-10

The effect of ER:YAG plus 5-fluorouracil on the outcome of punch grafting in nonsegmental vitiligo: a left–right comparative study


1 Department of Dermatology, Minia University, Minia, Egypt
2 Department of Dermatology, Zagazig University, Zagazig, Egypt
3 Department of Pathology, Zagazig University, Zagazig, Egypt

Date of Submission30-Nov-2015
Date of Acceptance28-Apr-2016
Date of Web Publication22-Nov-2016

Correspondence Address:
Tag S Anbara
Dermatology Department, Minia University Hospital, Minia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-6530.194154

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  Abstract 

Introduction Histopathologically, in vitiligo lesions, functioning melanocytes are absent and the inflammatory infiltrate is usually minute and trivial. Among the surgical methods used is minigrafting, which is considered the safest and easiest by many practitioners. Best results were obtained in segmental type and in the lesions involving the face. Application of topical 5-fluorouracil (5FU) on ER : YAG-ablated skin had been previously used with success in treating vitiligo lesions even in difficult-to-treat areas such as the fingers.
Aim of the study In this study, we tried to explore the effect of the prior application of 5FU on ER : YAG-ablated skin on the outcome of punch grafting in lesions that were unresponsive to phototherapy and were known to have moderate prognosis with surgery.
Patients and methods The study was a prospective left–right comparative study that was carried out on 20 patients with nonsegmental vitiligo who were in need for surgery after the exclusion of facial and periungual lesions. Histopathological and immunohistochemical comparison between the two modalities were also made using the sequential biopsy technique.
Results The clinical outcome was significantly better on the site pretreated with ER : YAG laser ablation and 5FU (P=0.001). Inflammatory cells in the form of dermal CD4+ and CD8+ cells were present in all operation sites showing depigmentation (32 lesions). Of them, 28 cases (87.5%) showed invasion of the lower layers of the epidermis in close proximity to the melanocytes by the CD8+ cells. Histopathological and immunohistochemical results were similar on both sides.
Conclusion The prior application of 5FU on ER : YAG-ablated skin yields better clinical results that were not explained by the histopathological findings. We suggest that both mechanical and immunologic mechanisms were involved in the process of repigmentation on using this manoeuvre.

Keywords: depigmentation, 5-fluorouracil,inflammation, pigmentation, punch grafting, t cells, vitiligo


How to cite this article:
Anbara TS, El-Ghareebb IM, Assafc MI, Abdel-Rahmana AT, El-Khayyata MA, Albalatb WA. The effect of ER:YAG plus 5-fluorouracil on the outcome of punch grafting in nonsegmental vitiligo: a left–right comparative study. Egypt J Dermatol Venerol 2016;36:4-10

How to cite this URL:
Anbara TS, El-Ghareebb IM, Assafc MI, Abdel-Rahmana AT, El-Khayyata MA, Albalatb WA. The effect of ER:YAG plus 5-fluorouracil on the outcome of punch grafting in nonsegmental vitiligo: a left–right comparative study. Egypt J Dermatol Venerol [serial online] 2016 [cited 2020 May 31];36:4-10. Available from: http://www.ejdv.eg.net/text.asp?2016/36/1/4/194154


  Introduction Top


Application of 5-fluorouracil (5FU) after mechanical dermabrasion was introduced, as a treatment for vitiligo, by Tsuji and Hamada (1983) [1]. Erbium-YAG (ER : YAG) laser with its controlled ablation, especially on irregular surfaces, was considered superior to mechanical dermabrasion [2]. Thus, a modification of the technique using an ER : YAG laser instead of the mechanical dermabrasion together with 5FU application was used successfully in treating periungual vitiligo [3]. This technique together with NB-UVB was found to be more effective compared with NB-UVB alone in a right–left comparative study. The combination of both treatment modalities proved to be effective in difficult-to-treat areas and to accelerate the repigmentation response [4].

Autologous tissue or cellular grafting in vitiligo is an option for repigmentation in patients with stable vitiligo, which is refractory or partially responsive to medical treatment [5]. Among these methods, punch grafting is considered the easiest, fastest, safest and least aggressive means of vitiligo surgeries [6]. As in other surgical treatments, patients should have no history of hypertrophic scars, keloid or bleeding disorders [7]. The allowed lesion size suitable for surgery are those involving less than 20% of the body surface area [8].

Despite fulfilment of all of the guidelines for surgical treatment in vitiligo, the outcome differs due to other factors. The best results are obtained in segmental vitiligo lesions [9] and those involving the face [10],[11],[12].


  Aim of the work Top


In the present work we tried to explore the effect of the prior use of 5FU application on ER : YAG laser-ablated lesions on the outcome of minigrafting in vitiligo lesions that were resistant to phototherapy. The patients were in need for surgery despite that their prognosis was not expected to be excellent due to the exclusion of segmental and facial lesions. Histopathological and immunohistochemical comparison between the sequence of events in the two groups was also made.


  Patients and methods Top


Study design

The study was a prospective left–right comparative study.

Patients

A total of 20 adult patients were included in the study.

Inclusion criteria

Patients with nonsegmental vitiligo who had at least two lesions in a symmetrical distribution were included in the study. All patients were not responding to NB-UVB phototherapy from the start or stopped improvement for the past 3 months after an initial response.

Exclusion criteria

Patients with segmental vitiligo, patients who received other treatment modalities in the past 3 months before the study, patients with bleeding or keloid tendencies, pregnant or lactating women and children were excluded from the study. Our study plan was to include the difficult-to-treat lesions but not the ones known to have almost no response after surgery; thus, the periungual areas were excluded. Besides, lesions with expected excellent response − namely, the face and those of segmental vitiligo − were also excluded.

Ethical consideration

The study was approved by the Faculty of Medicine Council. Each patient signed a written consent form to be included in the trial and to be photographed. The nature of the treatment and possible benefits and side effects were carefully explained to each patient.

Therapy

The treatment sides were randomly chosen. The method of randomization used in our study was the random number allocation, which was designed before the start of the study. One side was treated with ER : YAG laser ablation and 5FU application, followed by punch grafting (group I), whereas the other side was treated with punch grafting alone (group II).

On the side subjected to the erbium laser and 5FU therapy, a thick layer of a local anaesthetic cream (Emlas; AstraZeneca AB, Södertälje, Sweden) was applied to the treatment area under occlusion 30–40 min before starting the manoeuvre. The planned treatment area was designed not to exceed 30 cm2, to minimize patient discomfort during ablation and subsequent dressings. The affected skin was sterilized with povidone iodine and dried with sterilized gauze. The laser used was a Fidelis XS ER : YAG laser (Fotona Medical Lasers, Ljubljana, Slovenia). The hand piece was used with a spot size of 3–5 mm and a fluency of 300–500 mJ/cm2 according to the size of the lesion and the skin thickness of the affected area. Flurouracil 5% cream was then applied and the treated area was covered with sterilized gauze dressing. Daily dressings using 5FU cream covered with sterilized gauze were applied until a stage of inflammation with erythema, moderate oozing and crustations was reached. At this point, application of 5FU was stopped and daily topical antibiotic cream covered with gauze was applied until complete re-epithelization.

Punch grafting was started for both sides simultaneously after complete re-epithelization of the lesions on the laser side. Punch grafts were performed using a 2 mm punch. The donor and recipient sites were prepared using povidone iodine, and anaesthesia was achieved using lidocaine hydrochloride 2% solution without epinephrine (Xylocaine; AstraZeneca AB), with a 5-ml syringe and 30-G needle. Autologous minipunch grafts were harvested from the donor site (buttocks) to a  Petri dish More Details containing physiological saline and then were placed on the donor site. After graft transfer, the dressings were applied to both donor and recipient sites in the form of topical antibiotic (Fusidic acid 2% cream; Leo Pharmaceuticals), Copenhagen, Denmark vaseline gauze, dry gauze and adhesive Elastoplast, which were then removed after 7 days.

Clinical outcome

The patients were examined weekly to check the graft taking, any repigmentation or depigmentation and for the detection of any complications.

Histopathology

One of the discarded vitiliginous punches harvested during the process of preparation of the recipient site on day 1 was used as a baseline. Sequential punch biopsies were taken on days 7 and 14, and if depigmentation started. All specimens were fixed in 10% neutral-buffered formalin and paraffin-embedded tissue blocks were prepared. Tissue sections of 3–4 μm were stained using the following:

H&E, for routine microscopic examination.

Immunohistochemical stains, for the detection of CD4 and CD8 T lymphocytes.

Immunohistochemical staining

Formalin-fixed, paraffin-embedded tissue sections were exposed to the primary monoclonal antibodies directed against CD4 and CD8 cells (Bio Genex, San Ramon, California, USA). Antigen–antibody reaction was visualized using diaminobenzidine. Finally, the tissue sections were counterstained with Mayer’s hematoxylin solution (Merck) and examined using light microscopy.

Statistical analysis

Data were checked, coded, entered and analysed using SPSS software products Inc., Chicago, USA (the Statistical Package for Social Sciences) version 13.0 software for descriptive statistics and significance rates.


  Results Top


This study was carried on 20 patients, 14 male and six female. Their ages ranged between 18 and 55 years, with a mean and SD of 32.35+11.59 years.

The outline of the study and its clinical outcome are summarized in [Figure 1].
Figure 1: The study outline and its clinical outcome.

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Clinical results

Repigmentation of vitiligo lesions occurred in eight out of 40 lesions (20%), and the rest of the lesions [32 (80%)] showed no response and the grafts were depigmented. Six out of 20 sites (30%) in group I [Figure 2]a and [Figure 2]b and two out of 20 sites (10%) in group II [Figure 2]c and [Figure 2]d showed repigmentation. It is worthy to note that the two patients who responded to punch grafting alone on one side also responded to the combined treatment on the other side. χ2-Testing showed that group I had statistically significantly better clinical response compared with group II (χ2=16.00 and P=0.001).
Fgiure 2: (a) Symmetrical vitiligo lesions on forearms before treatment. (b) End results after 4 months. The clinical response and pigmentation were achieved after treatment with laser and 5-fluorouracil, but not with punch grafting only. (c) Symmetrical vitiligo lesions on the lower legs showed clinical response and pigmentation to both treatment modalities (d).

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We noticed that bleeding after punch grafting is more on the side pretreated with 5FU, and this can be stopped by compression for a short period. Moreover, the dissection of the skin cut using the punch was easier on the same side, especially on sites that are potentially difficult in dissection, such as the dorsa of fingers.

Histopathological results

Histopathological examination of biopsies taken from the vitiliginous lesions before treatment revealed absence of melanocytes and an upper dermal perivascular mononuclear infiltrate of mild-to-moderate intensity. Immunohistochemical staining of the infiltrate showed that about 40% of the perivascular mononuclear infiltrate within the papillary dermis was CD4 and about 20% was CD8 [Figure 3]a and [Figure 3]b.
Figure 3:Vitiligo skin biopsy (a) showing perivascular CD4+ cells in the reticular dermis, and CD8-stained biopsy (b) showed positive perivascular cells but less than CD4. One week after grafting, anti-CD4-stained biopsy (c) showed perivascular and interstitial positive cells, and it was negative for CD8 (d). Two weeks after grafting, deep dermal CD4+ cells (e) and dermal CD8+ cells (f), which were less in number compared with CD4 cells, were reported. (g) Depigmented graft showing CD8+ cells near melanocytes, and these cells (h) were seen scattered in the upper dermis in other depigmented grafts [diaminobenzidine (DAB) ×200].

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On sequential biopsies, after grafting, the changes in the type of infiltrate were the same in both groups on the first and second weeks, although they were different at the time of depigmentation [Table 1]. It was found that, in biopsies taken at the start of depigmentation, the dermal CD4+ cells that were present in the first and second weeks showed obvious increase in their number. Meanwhile, CD8+ cell infiltrate that was absent in biopsies of the first week showed marked increase outnumbering CD4+ cells. In all cases showing depigmentation (32 cases), CD8+ cells were detected in the dermis. Twenty-eight cases of them (87.5%) showed invasion of the lower layers of the epidermis in close proximity to the melanocytes by the CD8+ cells.
Table 1: Immunohistochemical results

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  Discussion Top


The treatment of vitiligo depends on recruitment of functional melanocytes into the affected area through horizontal, vertical and remote migration [9]. The latter can be carried out through autologous transplantation methods [13]. Surgery in generalized vitiligo has two positions: first, the areas that are classified as nonresponsive to medical treatments and phototherapy − for example, areas with anatomically scanty hair and areas with white hairs, and, second, the lesions expected to respond to medical treatment and phototherapy but showed no response after 6 months or stopped to respond after an initial response despite continuation of treatment for 3 successive months [8]. In both conditions, the patients urgently require surgery as the only available option for repigmentation.

In this work we included 20 patients with generalized symmetrical vitiligo, with areas resistant to phototherapy, excluding facial and segmental lesions with its known excellent response to surgery. Periungual lesions were also excluded because the surgery in these areas is usually useless. The exclusion of those patients with expected outcome makes the results of the current study less biased as factors other than the applied treatment were excluded. Patients were treated with the prior application of 5FU on ER : YAG-ablated skin followed by punch grafting on one side and with punch grafting only on the other side. These inclusion and exclusion criteria of patients led to the findings that the overall repigmentation after punch grafting in both groups was lower (20%) than that reported in previous studies [14],[15].

The difference in the clinical response between two groups was significant (P=0.001), denoting that the prior application of 5FU on ablated skin before punch grafting improves the repigmentation outcome. T-cell infiltrates in vitiligo have long been overlooked because they are minute [16]. Thus, frequent failure of early studies to demonstrate inflammatory changes in vitiligo led many investigators to consider the disease as noninflammatory [17]. Abdallah et al. (2003) [18] conducted a sequential immunohistochemical study of depigmenting and repigmenting minigrafts in six vitiligo patients to increase the opportunity to detect such inflammation. In our study, we applied the same technique to follow the changes occurring after punch grafting in 20 patients with and without the prior use of ER : YAG laser and topical 5FU and to correlate these changes with the clinical outcome.

Biopsies taken from the grafts at different stages of the study showed that the CD4+ cells in the dermis, which were present in the first and second weeks in small numbers, showed obvious increase at the start of depigmentation. Meanwhile, CD8+ cell infiltrate, which was absent in biopsies of the first week and started to appear on the second week, outnumbered CD4+ cells at the start of depigmentation. These findings confirmed the importance of the inflammation in the depigmentation process and showed that inflammation is a common finding in vitiligo in contrary to what was reported before. We suggest that failure of other researchers to detect the inflammatory infiltrate in vitiligo was due to the improper biopsy timing. We also suggest that, although the presence of the CD4+ cells in our biopsies is an important finding, they are not concerned with direct destruction of melanocytes because they are always away from the site the melanocytes. Meanwhile, the CD8+ cells, which were found in close apposition of the basal cells, are the incriminated group in the process of melanocyte destruction.

In the current study, CD8+ cells were detected in all depigmented cases, but the attack of the lower epidermis was detected in 87.5% of those cases. This might be due to the miss of the attack in the remaining 12.5% of cases in the interval between the biopsies, which points to the short-term nature of the inflammatory process. It is worthy to note that CD8+ cells that were absent on the first week and started to appear on the second week after punch grafting were present in biopsies taken at the baseline from the recipient stable lesions, denoting its role as a marker of previous depigmentation attack.

Despite the difference in the clinical outcome, the histopathological findings were similar in both groups. Inflammation induced by 5FU application was observed clinically in the form of erythema, oozing and crustation. It goes without saying that this clinical reaction will be presented by an inflammatory response if a biopsy was performed at that time; however, because our study protocol was to perform the biopsy at similar situations in both groups, biopsies were performed after complete re-epithelization. Although in vitiligo the inflammatory reaction occurs at the dermoepidermal junction in both groups, this does not rule out our assumption that the expected earlier inflammation induced by 5FU might sequestrate and exhaust the vitiligo immune response, which was reflected clinically by a better response in the group pretreated with 5FU.

This immunologic proposition is supported by the reported findings on the effect of cytokines, chemokines and other immunologic products on depigmentation and repigmentation processes (e.g. interferon-γ [19], tumor-necrosis factor-α [20,21], interleukin-6 and interleukin-8 [22], leukotrienes C4 and D4, hepatocyte growth factor, stem cell factor and basic fibroblast growth factor [23],[24]).

A second mechanism might be involved as well, which is the mechanical one. This simply acts through increasing the intercellular spaces, which facilitates the melanocyte migration.

This view was supported by two recent studies in which the effect of the microenvironment around the melanocytes on their ability to migrate and function was demonstrated. These studies reported that when the environment around the melanocytes were more compact (e.g. by fibrosis) the melanocyte migration was difficult, whereas when it was less compact (e.g. by widening the intercellular spaces) the migration was easier. In the first one, Kovacs et al. (2015) [25] proved that the repigmentation observed on areas between the punch grafts was due to true migration and activation of the melanocytes from the punch grafts. They reported that lower numbers of melanocytes were counted on samples collected from punch grafts, which showed cobble stoning. In contrast, Gauthier et al. (2013) [26] carried out the second study on the skin of seven guinea pigs: three were treated with mechanical dermabrasion plus topical 5FU in an achromic area contiguous to a pigmented area; two were treated with dermabrasion only in a similar area; and two were treated with topical 5FU alone. Clinical, histological and ultrastructural studies were performed. Evident pigment spread from the pigmented into the achromic area was only reported in the group treated with dermabrasion plus 5FU after 2 months. The authors proposed that the degenerative keratinocytes and enlarged intercellular spaces of the basal layer allowed the active melanocytes to migrate easily through these enlarged spaces and they confirmed their findings with the electron microscope.

In our study, we suggest that both mechanisms were involved; topical application of 5FU on the ablated skin induced an inflammation, which acted mechanically, by opening the intercellular spaces and releasing inflammatory mediators, and acted immunologically through the sequestration of the inflammatory cells attacking the melanocytes to a higher level. Both mechanisms facilitated the trafficking for the melanocyte migration from the punch grafts towards the achromic skin.


  Conclusion Top


This study proves that inflammation, which occurs as a short-term event, is crucial in vitiligo. The prior application of 5FU on ER : YAG-ablated skin yields better clinical results that were not explained by the histopathological findings. We suggest that the process of re-pigmentation after punch grafting in vitiligo is mastered by two mechanisms: immunological and mechanical. The results of this study together with the above-mentioned recent studies points towards the role of 5FU in the manipulation of both mechanisms. This new manoeuvre offers a new surgical tool to manage the category of difficult-to-treat vitiligo areas.

Acknowledgements

The authors confirm that the manuscript titled as ‘The effect of ER : YAG plus 5-flurouracil on the outcome of punch grafting in nonsegmental vitiligo: a left–right comparative study’ has been read and approved by all authors and that the requirements for authorship have been met. The manuscript represents an honest work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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