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The content of short chain fatty acids in the jejunal digesta, caecal digesta and faeces of growing pigs
ORIGINAL STUDY
Clinicopathologic Analysis of Stable and Unstable Vitiligo: A Study of 66 Cases Amit Kumar Yadav, MD,* Priyanka Singh, MD,† and Niti Khunger, MD†
Abstract: Vitiligo is an acquired skin disorder characterized by milky-white macules and absence of functioning melanocytes. The cornerstone of its management is the correct categorization of a case into its 2 broad types—stable and unstable vitiligo. This distinction is at present based mainly on clinical criteria because the histopathological features are not fully established. This study was thus undertaken to examine histopathological features of vitiligo and to come up with a reliable and systematic approach toward this diagnostic challenge. All patients presenting with clinical features of vitiligo at our institution were included in the study. A 3-mm punch biopsy was taken from 3 sites—lesional, perilesional, and normal skin. Histopathological examination was primarily focused on evaluating 5 histopathological variables—spongiosis, epidermal lymphocytes, basal cell vacuolation, dermal lymphocytes, and melanophages. A total number of 66 patients were included in the study. There were 30 patients in stable and 36 in unstable vitiligo groups. It was observed that all 5 histopathological pattens were associated with unstable vitiligo. All the cases were then scored using a scoring system devised by the authors and the scores obtained were correlated with clinical categorization. It was observed that while there is a definite overlap in histological findings in the 2 groups, adoption of a systematic reporting system brings more consistency and objectivity in the diagnosis. The authors have recommended diagnoses that should be reported for the various scores. This in turn will help us to more reliably and confidently manage these patients. Key Words: vitiligo, stable, unstable, histopathology, scoring system (Am J Dermatopathol 2016;0:1–6)
INTRODUCTION Vitiligo is an acquired, multifactorial, depigmenting disorder of the skin characterized clinically by milky-white macules and histopathologically by an absence of functional melanocytes in the affected area.1 It equally affects both sexes with a worldwide prevalence of 0.1%–2%.1 The prevalence of vitiligo has been reported to be higher in India.2 It may appear at any time from birth to senescence, although the onset is most commonly observed in persons aged 10–30 years. It has a profound psychosocial impact3 and greatly affects the From the Departments of *Pathology, and †Dermatology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India. The authors declare no conflicts of interest. Reprints: Amit Kumar Yadav, MD, Assistant Professor, Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India 110029 (e-mail: [email protected]). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Am J Dermatopathol Volume 0, Number 0, Month 2016
quality of life, particularly in the Indian context, owing to the social stigma attached to it. Vitiligo is usually classified into 2 broad types, namely: stable and unstable vitiligo. The natural course to a large extent depends on the type of vitiligo. Stable vitiligo usually has a chronic slowly progressive course. Many patients may show an initial period of activity followed by variable period of quiescence. The patients with unstable vitiligo usually have a rapid progression after an abrupt onset, which later on may become stable. Stability in vitiligo means an absence of new lesions, increase in the size of preexisting macules, and new onset Koebners phenomena over a period. However, there is no consensus on the period of stability, and it varies from 4 months to 3 years, according to different authors.4 Recently, Indian Association of Dermatologists, Venerelogists and Leprologists taskforce, in their consensus recommendation, has defined the period of stability to be at least one year.5 By this definition, a vitiligo patient is considered to have an unstable disease if there is any sign of the above-mentioned activity within the last one year. Stability is the decisive factor and cornerstone of vitiligo therapy. It has many bearings on the choice of treatment modality for vitiligo. There have been many reports of worsening of unstable vitiligo by photochemotherapy. Stability is the major criterion for selecting a patient for surgical treatment in vitiligo.5,6 Unstable vitiligo cases are not suitable for surgical approach to even localized lesion, as there are higher chances of failure of grafts or transplants and, at times, even the donor area may get depigmented. Currently this distinction is primarily based on clinical criteria. The VIDA score (vitiligo disease activity score) suggested by Njoo et al,7 is based on long-term (upto 1 year) observation of clinical activity in experimentally-induced Koebners phenomena. This is not feasible in a routine clinical setting. The Test Graft method proposed by Falabella et al8 is invasive and inconsistent. The role of histopathology is still not well established. Some authors have suggested the role of histopathology and immunohistochemistry in predicting stability.9–12 However, there are only limited studies which have tried to explore the utility of histopathology in solving this diagnostic dilemma. The results of these studies have been inconsistent, thus making the distinction between stable and unstable vitiligo difficult on histopathological grounds. Therefore this study was undertaken, to evaluate the histopathological features of stable and unstable vitiligo. The objective is to produce a reliable and systematic histopathological approach to solve this diagnostic dilemma. Where necessary www.amjdermatopathology.com |
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the histopathological findings have been correlated with clinical features so as to reach a logical conclusion. The outcomes of the study are expected to influence treatment outcome as histopathological examination may help to predict the prognosis with more accuracy in these cases.
MATERIAL AND METHODS This study was a cross-sectional study conducted in the departments of Dermatology and Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi from October 2012–February 2014. The study was duly approved by institutional ethics committee. An informed consent was taken from all the patients who participated in the study. All patients presenting with clinical features of vitiligo in outpatient wing of department of dermatology, Safdarjung hospital, which were either newly diagnosed cases or have stopped treatment in the last 3 months were included. The patients were divided into 2 groups, ie, stable and unstable vitiligo as per recommendations of the Indian Association of Dermatologists, Venerelogists and Leprologists taskforce. A patient with no history of progression of existing lesions and/ or onset of new lesion and absence of Koebner phenomena for a period of past 1 year was included in stable vitiligo group. On the contrary, patients with history and clinical features suggesting progression of the existing lesions and/or appearance of new lesions and presence of new onset Koebner phenomena were included in unstable vitiligo group. The patients that were excluded from the study were those not willing to give consent for the study, refusing skin biopsy, currently on any treatment of vitiligo, presenting with either pure mucosal type or universal type of vitiligo, chemical leukoderma, depigmentation due to burns or trauma, and herpes simplex-induced leukoderma. In case of each patient, meticulous history and clinical examination was performed. Based on history and clinical examination, 2 groups were formed ie, stable and unstable vitiligo group. After the clinical evaluation, a punch biopsy was taken from a representative lesion. A 3-mm punch biopsy was taken from 3 sites:
The biopsy specimens were placed in 10% neutralbuffered formalin as fixative media before transporting it to the department of pathology for further processing. All the findings including histopathology report, were documented on a preformed standard proforma. A total of 5 variables were selected for histopathological evaluation. Of these, 3 included epidermal changes, ie, spongiosis, epidermal lymphocytes, and basal layer vacuolization, whereas the rest of the 2 were dermal changes ie, dermal lymphocytes and melanophages. These findings were selected based on the previous works of Benzekri9 and Sharquie et al.11 However, in the previous studies dermal lymphocytes were subjectively assessed. Therefore, to make the evaluation of dermal lymphocytes more objective, the authors counted them throughout the section. This was performed on a monitor attached to a video-camera viewing through a ·20 objective of attached microscope. Evaluation of biopsy specimen was blind and the evaluator was not aware of the clinical classification of the cases. The histological findings were then correlated with the clinical picture in each case. Statistical analysis was performed by Fisher exact test and Pearson x2 test using IBM SPSS statistics v21.0.
RESULTS
The choice of macule for biopsy depended on the nature of vitiligo. In case of stable vitiligo, margin of a representative macule was selected for biopsy. In case of unstable vitiligo, a macule which was either increasing in size or had newly appeared within 1 year of clinical presentation was selected. If more than one macules had appeared in the past year, then the most recent onset macule was selected. If the 2 conditions existed simultaneously, ie, some macule had been increasing in size and some had newly appeared within past 1 year, then most recent onset macule of appropriate size was selected for biopsy.
The study included 66 patients. Of the 66 patients, 29 were female (43.94%) and 37 were males (56.06%). M:F ratio was 1.3:1. There were 30 patients in stable vitiligo (Fig. 1A) group which included 16 males and 14 females. The unstable vitiligo (Fig. 1B) group consisted of 36 patients among whom there were 21 males and 15 females. The 2 groups were compared by Fisher exact test (P-value = 0.804). Thus, there is no significant difference between number of male and female patients in either of the groups. The patient’s age at presentation ranged from 7 to 56 years. Most patients (n = 26) were in the age group 17–26 years (39.4%). On comparing the age-distribution in the 2 groups, the most common age group at presentation was same in both groups, ie, 17–26 years. The most common age group at onset was 3–13 years and the least common was 43–53 years. Patients were further divided into stable and unstable groups based on their age group. The most common age group at onset in stable vitiligo group was 13–23 years, whereas that of unstable vitiligo group was 23–33 years. The age of onset was not found to be significantly associated with disease activity (P-value = 0.328). The mean duration between onset and presentation, in the 2 groups was analyzed. The mean 6 2 SD duration in unstable vitiligo group was 6.7 6 5.4 years, as compared with 11.8 6 8.2 years, in the stable group. This difference was statistically significant (P-value = 0.005). This implies that vitiligo shows trend toward instability with shorter duration between age of onset and presentation. The most common site of onset was legs (n = 26) followed by face (n = 22). Site of onset in the stable and unstable groups was further examined. The site of onset of vitiligo which was significantly and consistently associated with stability came out to be trunk and that associated with unstable group was hands (x2 test, P-value = 0.007). Positive family history of vitiligo was present in 9 (13.6%) patients of a total
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1. Margin of the representative lesion (totally inside the macule). 2. Perilesional area, which was taken to be roughly within 5 cm from the margin of the lesion. 3. Normal skin taken more than 5 cm away from the lesion margin.
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Clinicopathologic Analysis of Vitiligo
FIGURE 1. Clinical picture of vitiligo cases (A) stable vitiligo (B) unstable vitiligo.
66 patients. Family history was not significantly associated with disease activity (Fisher exact test, P-value = 0.721). Repigmentation of vitiligo macules was noticed in both the groups, ie, stable and unstable vitiligo. It was not found to be a significant predictor of disease stability (Fisher exact test, P-value = 0.059). Regression in size of the existing vitiligo macules, was seen in 16 patients, ie, almost half of stable cases (53.3%), and only in 8 patients (22.2%) of unstable vitiligo. The association of regression of lesions with stable disease was statistically significant (Fisher exact test, P-value = 0.011). In
unstable cases, wherever some lesions showed regression, simultaneous increase in size of other lesions and/or occurrence of new lesions was also noticed. Increase in the size of preexisting lesions in the unstable vitiligo group was present in 34 (94.4%) patients, whereas it was absent in all the patients of stable vitiligo group. New onset lesions were seen in 27 (75%) of 36 unstable vitiligo cases and none in stable cases. Biopsies were taken from 3 sites, ie, lesional, perilesional, and normal skin. The histopathological analysis was perfomed by a pathologist who was not aware of the clinical
FIGURE 2. Histopathological variables evaluated (A) spongiosis, (B) epidermal lymphocytosis, (C) basal cell vacuolation, (D) dermal lymphocytes. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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features. The histological parameters that were observed in each case were spongiosis (Fig. 2A), epidermal lymphocytes (Fig. 2B), and basal layer vacuolization (Fig. 2C) in the epidermis and dermal lymphocytes (Fig. 2D) along with melanophages in the dermis. While evaluating dermal lymphocytes, the cases were divided into 2 subcategories, ie, those with ,100 and .100 dermal lymphocytes. The results are summarized in Table 1. In the lesional skin, all the 5 histological variables were more frequently associated with clinically active disease. It was observed that the presence of spongiosis (P-value = 0.001), epidermal lymphocytes (P-value = 0.001), basal layer vacuolization (P-value = 0.033), and presence of more than 100 dermal lymphocytes (P-value , 0.0001) were individually significantly associated with unstable vitiligo suggesting them to be important histological predictors of disease activity. Histological examination of biopsy from perilesional area showed similar findings as those observed in lesional skin. All the findings were more common in unstable cases. Of these, the presence of spongiosis (P-value = 0.005), epidermal lymphocytes (P-value = 0.017), and more than 100 dermal lymphocytes (P-value = 0.002) were significantly associated with disease activity. The normal appearing skin in none of the 66 patients of vitiligo showed any of the abovementioned findings. However, few dermal lymphocytes were seen in all of them, which was always ,100 in each case. Although, the statistical analysis does point toward certain histological features which point toward stability or vice-versa but their assessment is subjective. Thus, these may not be helpful in routine histopathological reporting. Thus, to bring more objectivity into the histological assessment of these cases, all the 5 histological parameters were scored using a scoring system as shown in Table 2. The results of the scoring were then correlated with the clinical categorization. This correlation is shown in Table 3.
DISCUSSION Vitiligo is an enigmatic disease with varied clinical presentations and an unpredictable course. The basic defect is loss of functional melanocytes. However, the exact reasons for this are not entirely understood. The various theories that have been suggested, include cell mediated autoimmunity,13 humoral immunity,14 altered cellular metabolism,15 and melanocytorrhagy.16,17 The diagnosis of vitiligo is primarily based on clinical examination. However, other causes of hypopigmentation such as pityriasis alba, eczema or hypopigmented
mycosis fungoides should be confidently ruled out. These act as potential caveats in the diagnosis of vitiligo. In cases where there is uncertainty on clinical examination, a clinicopathological correlation is extremely important. The treatment outcome in vitiligo remains unpredictable too, more so, of nonsurgical approach. Surgical modalities may have negative outcomes, if patient selection is not performed properly. Till date, there is no single reliable tool that can consistently predict stability or activity of this disorder. However, this knowledge is of utmost importance in selection of the treatment modality, predicting treatment outcome and explaining prognosis to the patients. Many attempts in this context have been made in the past. There are a variety of methods suggested for this by different workers which include, absence of new lesion by history, no extension of old lesions, experimentally-induced koebnerization,7 vitiligo disease activity scoring,5 test minigrafting,6 biochemical parameters,18 ie, catecholamines level, antioxidants status, serum homocysteine levels, serological parameters, histopathology,9 and immunohistochemistry.12 Most of these, especially biochemical and serological parameters are cumbersome, unavailable, confined to research laboratories, and without any well-defined cut-off levels. The minigrafting test and experimentally induced koebnerization are invasive, not feasible, and inconsistent. This study was undertaken to evaluate the histopathological features of stable and unstable vitiligo. The objective was to come up with a reliable and systematic histopathological approach to solve this clinically-crucial diagnostic dilemma. The most accepted definition of stable vitiligo among many authorities remains as minimum one year of inactivity.19 Based on this history, 2 groups were formed, ie, stable and unstable vitiligo groups. Other parameters from history were studied to find significance of their association with stability. The sex and age of onset did not help in predicting activity of vitiligo, nor does the age at presentation. These findings are in concordance with the study by Hann et al,20 as they also reported that sex and age of onset don’t reliably differentiate progressive from nonprogressive vitligo. A negative family history was not found to be significantly associated with stability. This is in contrast to the study by Pajvani et al,21 in which a negative family history was significantly associated with regressive course of vitiligo. Trunk was significantly associated with stable vitiligo and hand was significantly related to unstable vitiligo. This finding can be explained on the basis of koebner phenomena because hands are the most trauma-prone site of body. This
TABLE 1. Summary of Histological Findings in Stable and Unstable Vitiligo Groups Stable Vitiligo S. No.
Histopathological Feature
1. 2. 3. 4. 5. 6.
Spongiosis Epidermal lymphocytes Basal vacuolization Dermal lymphocyte (.100) Dermal lymphocyte (,100) Melanophages
4
Lesional n (%) 1 1 1 1 29 2
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(3.3%) (3.3) (3.3) (3.3) (96.7) (6.6)
Unstable Vitiligo
Perilesional n (%)
Normal n (%)
1 (3.3) 2 (6.6) Nil 1 (3.3) 29 (96.7) 1 (3.3)
Nil Nil Nil Nil 30 (100) Nil
Lesional n (%) 13 13 7 21 15 3
(36.1) (36.1) (19.4) (58.3) (41.7) (8.3)
Perilesional n (%) 10 10 2 14 22 2
(27.7) (27.7) (5.5) (38.9) (61.1) (5.5)
Normal n (%) Nil Nil Nil Nil 36 (100) Nil
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Clinicopathologic Analysis of Vitiligo
TABLE 2. Proposed Vitiligo Histological Scoring System S. No.
Histological Feature
1.
Spongiosis
2.
Epidermal lymphocytes
3.
Basal vacuolization
4.
Dermal lymphocytes .100
5.
Melanophages
Observation
Score
Present Absent Present Absent Present Absent Present Absent Present Absent
1 0 1 0 1 0 1 0 1 0
may lead to constant presence of trigger, resulting in activity of vitiligo for longer duration than at other sites of body. There is very few data available on histopathological changes in the 2 groups of vitiligo. Therefore, there are no firm histopathological criteria on which this distinction can be made with a reasonable degree of certainty. There are few reports of inflammatory elements in the marginal skin of patients with vitiligo.11 These changes consist of focal epidermal and follicular inflammatory cell infiltration, superficial dermal perivascular and perifollicular mononuclear infiltrate. These changes are more avidly seen in unstable vitiligo as compared with stable disease. In this study, similar histopathological changes were studied and correlated with disease activity by history and clinical examination. In both, lesional and perilesional skin biopsies, epidermal changes, ie, spongiosis and presence of epidermal lymphocytes were significantly associated with disease activity as evident by history. Similarly, dermal infiltration was also significantly associated with active vitiligo in the biopsy specimens of both the areas. Basal layer vacuolization was significantly higher in unstable vitiligo group in lesional biopsies but not in perilesional ones. The above findings are in concordance with the study by Sharquie et al.11 The role of immunohistochemistry in vitiligo has been examined by few studies in the past. These studies have primarily focused on the characterization of inflammatory infiltrate in vitiligo. Badri et al10 showed an increase of CD3, CD4 and CD8 positive T cells in cases of vitiligo. Their findings suggest that T cells mediate the autoimmune destruction of melanocytes in vitiligo. In an another study, Ahn TABLE 3. Correlation of Proposed Vitiligo Histological Scoring System With Stable and Unstable Vitiligo S. No. 1. 2. 3. 4. 5. 6.
Total Score
Stable Vitiligo n (%)
5 4 3 2 1 0
Nil Nil 1 (2.8) 4 (11.1) 7 (19.4) 24 (66.7)
Unstable Vitiligo n (%) 3 3 8 10 6
Nil (10) (10) (26.7) (33) (20)
Confidence Interval 1.5 2 6 8.5 15
Nil 6 4.1 6 1.9 6 2.2 6 1.5 6 6.4
P-value = 0.4.
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et al12 examined the marginal skin of unstable and stable vitiligo using ICAM-1, HLA-DR, CD4, and CD8 monoclonal antibodies. ICAM-1 expression in epidermis was seen only in unstable group, whereas dermal ICAM-1 was expressed in both the groups. HLA-DR epidermal and dermal expression was seen in both groups. CD4 lymphocytes were expressed more strongly in unstable group. However, no difference in CD8 lymphocytes was seen in the 2 groups. Le Poole et al22 studied the inflammatory infiltrate within perilesional skin of 3 cases of unstable vitiligo. They found that epidermis-infiltrating T cells exhibit an increased CD8/CD4 ratio and increased cutaneous lymphocyte antigen and interleukin-2 receptor expression. In perilesional dermis, CD68 + OKM5-macrophages were more numerous than in lesional or nonlesional skin. Wankowicz-Kalinska et al23 showed that CD4 and CD8 positive lymphocytes immunopolarized to type 1. They hypothesized that this may be related to the melanocyte loss seen in vitiligo. However, these previous observations by various authors do not permit differentiation between stable and unstable vitiligo because they are a result as opposed to the cause of the disease process. They also did not compare the results with cases of stable vitiligo. Thus, it can be concluded from previous studies that immunohistochemistry is unlikely to play a decisive role in the distinction between stable and unstable vitiligo. A conclusive diagnosis is more likely to be reached by correlating histomorphological findings with clinical features. Thus, the histological features were then correlated with clinical findings. On correlating with the type of margin, it was seen that spongiosis, lymphocytes, basal cell vacuolization in the epidermis, and increased dermal lymphocytes when present were strongly associated with an ill defined margin. This is in agreement with the work of Benzekri et al9 who have hypothesized that hypomelanotic vitiligo lesions with poorly defined borders could be the clinical expression of histological features found at the margin like spongiosis, basal layer vacuolization, and dermal infiltrates. However, vitiligo lesions with sharply demarcated borders are related to absence of these histologic changes. Based on the observations in this study, the authors propose a histological scoring system as shown in Table 2. Each parameter is scored in every case and a total score is obtained. The minimum score possible is 0 and maximum is 5. On applying the histological scoring system, the results obtained in the 2 groups are summarized in Table 3. As can be seen, there is a definite overlap in the histological findings in the 2 groups. However, certain conclusions can be drawn. Cases of stable vitiligo tend to have a lower score and those of unstable vitiligo a higher score. Based on the findings of the correlation of histological score with clinical features, the authors recommend that every case of vitiligo should be scored on these parameters. The final scores and their corresponding recommended diagnosis are presented in Table 4. It is hoped that the adoption of a systematic reporting of these cases will bring more consistency and objectivity in their diagnosis. This will help us to more reliably and confidently manage these patients. Thus to conclude, distinction between stable and unstable vitiligo is of crucial importance in the management www.amjdermatopathology.com |
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TABLE 4. Final Recommended Diagnosis on the Basis of Score S. No.
Total Score
1. 2. 3.
5 4 3
4.
2
5.
0–1
Recommended Diagnosis Unstable vitiligo Unstable vitiligo Favor unstable vitiligo, however, clinical correlation is essential Favor stable vitiligo, however, clinical correlation is essential Strongly favor stable vitiligo, however, clinical correlation is essential
of this condition. To achieve this, many attempts have been made in the past using a variety of methods. The role of histopathology in this direction is not entirely established. The authors have shown that using certain histological features and correlating them with clinical features, a diagnosis can be made in most cases. A novel histological scoring system along with recommended diagnostic categories has been proposed. It is sincerely hoped that this will bring objectivity and consistency in the diagnosis of these patients. REFERENCES 1. Halder RM, Taliaferro SJ. Vitiligo. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hills publications; 2008:616–619. 2. Handa S, Kaur I. Vitiligo: clinical findings in 1436 patients. J Dermatol. 1999;26:653–657. 3. Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes. 2003;1:58. 4. Lahiri K. Stability in vitiligo—whats that? J Cutan Aesthet Surg. 2009;2: 38–40. 5. Parsad D, Gupta S. Standard guidelines of care for vitiligo surgery. Indian J Dermatol Venereol Leprol. 2008;74:37–45. 6. Falabella R. Surgical treatment of vitiligo: why, when and how. J Eur Acad Dermatol Venereol. 2003;17:518–520. 7. Njoo MD, Das PK, Bos JD, et al. Association of the Koebners phenomena with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol. 1999;135:414.
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8. Falabella R, Arrunategui A, Barona MI, et al. The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation. J Am Acad Dermatol. 1995;32:228–232. 9. Benzekri L, Gauthier Y, Hamada S, et al. Clinical features and histological findings are potential indicators of activity in lesions of common vitiligo. Br J Dermatol. 2013;168:265–271. 10. Badri AM, Todd PM, Garioch JJ, et al. An immunohistological study of cutaneous lymphocytes in vitiligo. J Pathol. 1993;170:149–155. 11. Sharquie KE, Mehenna SH, Naji AA, et al. Inflammatory changes in vitiligo stage I and stage II depigmentation. Am J Dermatopathol. 2004;26:108–112. 12. Ahn SK, Choi EH, Lee SH, et al. Immunohistochemical studies from vitiligo: comparison between active and inactive lesions. Yonsei Med J. 1994;35:404–410. 13. van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, et al. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest. 2000;80:1299–1309. 14. Cui J, Arita Y, Bystryn JC. Cytolytic antibodies to melanocytes in vitiligo. J Invest Dermatol. 1993;100:812–815. 15. Dell’anna ML, Picardo M. A review and a new hypothesis for nonimmunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;19:406–411. 16. Gauthier Y, Cario Andre M, Taïeb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy? Pigment Cell Res. 2003;16:322–332. 17. Kumar R, Parsad D, Kanwar AJ. Role of apoptosis and melanocytorrhagy: a comparative study of melanocyte adhesion in stable and unstable vitiligo. Br J Dermatol. 2011;164:187–191. 18. Rao A, Gupta S, Dinda AK, et al. Study of clinical, biochemical and immunological factors determining stability of disease in patients with generalized vitiligo undergoing melanocyte transplantation. Br J Dermatol. 2012;166:1230–1236. 19. Yaghoobi R, Omidian M, Bagherani N. Vitiligo: a review of the published work. J Dermatol. 2011;38:419–431. 20. Hann SK, Chun WH, Park YK. Clinical characteristics of progressive vitiligo. Int J Dermatol. 1997;36:353–355. 21. Pajvani U, Ahmad N, Wiley A, et al. The relationship between family medical history and childhood vitiligo. J Am Acad Dermatol. 2006;55: 238–244. 22. Le Poole IC, van den Wijngaard RM, Westerhof W, et al. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol. 1996;148:1219–1228. 23. Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, et al. Immunopolarization of CD4+ and CD8+ T cells to Type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest. 2003;83:683–695.
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Clinicopathologic Analysis of Stable and Unstable Vitiligo: A Study of 66 Cases Amit Kumar Yadav, MD,* Priyanka Singh, MD,† and Niti Khunger, MD†
Abstract: Vitiligo is an acquired skin disorder characterized by milky-white macules and absence of functioning melanocytes. The cornerstone of its management is the correct categorization of a case into its 2 broad types—stable and unstable vitiligo. This distinction is at present based mainly on clinical criteria because the histopathological features are not fully established. This study was thus undertaken to examine histopathological features of vitiligo and to come up with a reliable and systematic approach toward this diagnostic challenge. All patients presenting with clinical features of vitiligo at our institution were included in the study. A 3-mm punch biopsy was taken from 3 sites—lesional, perilesional, and normal skin. Histopathological examination was primarily focused on evaluating 5 histopathological variables—spongiosis, epidermal lymphocytes, basal cell vacuolation, dermal lymphocytes, and melanophages. A total number of 66 patients were included in the study. There were 30 patients in stable and 36 in unstable vitiligo groups. It was observed that all 5 histopathological pattens were associated with unstable vitiligo. All the cases were then scored using a scoring system devised by the authors and the scores obtained were correlated with clinical categorization. It was observed that while there is a definite overlap in histological findings in the 2 groups, adoption of a systematic reporting system brings more consistency and objectivity in the diagnosis. The authors have recommended diagnoses that should be reported for the various scores. This in turn will help us to more reliably and confidently manage these patients. Key Words: vitiligo, stable, unstable, histopathology, scoring system (Am J Dermatopathol 2016;0:1–6)
INTRODUCTION Vitiligo is an acquired, multifactorial, depigmenting disorder of the skin characterized clinically by milky-white macules and histopathologically by an absence of functional melanocytes in the affected area.1 It equally affects both sexes with a worldwide prevalence of 0.1%–2%.1 The prevalence of vitiligo has been reported to be higher in India.2 It may appear at any time from birth to senescence, although the onset is most commonly observed in persons aged 10–30 years. It has a profound psychosocial impact3 and greatly affects the From the Departments of *Pathology, and †Dermatology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India. The authors declare no conflicts of interest. Reprints: Amit Kumar Yadav, MD, Assistant Professor, Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India 110029 (e-mail: [email protected]). Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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quality of life, particularly in the Indian context, owing to the social stigma attached to it. Vitiligo is usually classified into 2 broad types, namely: stable and unstable vitiligo. The natural course to a large extent depends on the type of vitiligo. Stable vitiligo usually has a chronic slowly progressive course. Many patients may show an initial period of activity followed by variable period of quiescence. The patients with unstable vitiligo usually have a rapid progression after an abrupt onset, which later on may become stable. Stability in vitiligo means an absence of new lesions, increase in the size of preexisting macules, and new onset Koebners phenomena over a period. However, there is no consensus on the period of stability, and it varies from 4 months to 3 years, according to different authors.4 Recently, Indian Association of Dermatologists, Venerelogists and Leprologists taskforce, in their consensus recommendation, has defined the period of stability to be at least one year.5 By this definition, a vitiligo patient is considered to have an unstable disease if there is any sign of the above-mentioned activity within the last one year. Stability is the decisive factor and cornerstone of vitiligo therapy. It has many bearings on the choice of treatment modality for vitiligo. There have been many reports of worsening of unstable vitiligo by photochemotherapy. Stability is the major criterion for selecting a patient for surgical treatment in vitiligo.5,6 Unstable vitiligo cases are not suitable for surgical approach to even localized lesion, as there are higher chances of failure of grafts or transplants and, at times, even the donor area may get depigmented. Currently this distinction is primarily based on clinical criteria. The VIDA score (vitiligo disease activity score) suggested by Njoo et al,7 is based on long-term (upto 1 year) observation of clinical activity in experimentally-induced Koebners phenomena. This is not feasible in a routine clinical setting. The Test Graft method proposed by Falabella et al8 is invasive and inconsistent. The role of histopathology is still not well established. Some authors have suggested the role of histopathology and immunohistochemistry in predicting stability.9–12 However, there are only limited studies which have tried to explore the utility of histopathology in solving this diagnostic dilemma. The results of these studies have been inconsistent, thus making the distinction between stable and unstable vitiligo difficult on histopathological grounds. Therefore this study was undertaken, to evaluate the histopathological features of stable and unstable vitiligo. The objective is to produce a reliable and systematic histopathological approach to solve this diagnostic dilemma. Where necessary www.amjdermatopathology.com |
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the histopathological findings have been correlated with clinical features so as to reach a logical conclusion. The outcomes of the study are expected to influence treatment outcome as histopathological examination may help to predict the prognosis with more accuracy in these cases.
MATERIAL AND METHODS This study was a cross-sectional study conducted in the departments of Dermatology and Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi from October 2012–February 2014. The study was duly approved by institutional ethics committee. An informed consent was taken from all the patients who participated in the study. All patients presenting with clinical features of vitiligo in outpatient wing of department of dermatology, Safdarjung hospital, which were either newly diagnosed cases or have stopped treatment in the last 3 months were included. The patients were divided into 2 groups, ie, stable and unstable vitiligo as per recommendations of the Indian Association of Dermatologists, Venerelogists and Leprologists taskforce. A patient with no history of progression of existing lesions and/ or onset of new lesion and absence of Koebner phenomena for a period of past 1 year was included in stable vitiligo group. On the contrary, patients with history and clinical features suggesting progression of the existing lesions and/or appearance of new lesions and presence of new onset Koebner phenomena were included in unstable vitiligo group. The patients that were excluded from the study were those not willing to give consent for the study, refusing skin biopsy, currently on any treatment of vitiligo, presenting with either pure mucosal type or universal type of vitiligo, chemical leukoderma, depigmentation due to burns or trauma, and herpes simplex-induced leukoderma. In case of each patient, meticulous history and clinical examination was performed. Based on history and clinical examination, 2 groups were formed ie, stable and unstable vitiligo group. After the clinical evaluation, a punch biopsy was taken from a representative lesion. A 3-mm punch biopsy was taken from 3 sites:
The biopsy specimens were placed in 10% neutralbuffered formalin as fixative media before transporting it to the department of pathology for further processing. All the findings including histopathology report, were documented on a preformed standard proforma. A total of 5 variables were selected for histopathological evaluation. Of these, 3 included epidermal changes, ie, spongiosis, epidermal lymphocytes, and basal layer vacuolization, whereas the rest of the 2 were dermal changes ie, dermal lymphocytes and melanophages. These findings were selected based on the previous works of Benzekri9 and Sharquie et al.11 However, in the previous studies dermal lymphocytes were subjectively assessed. Therefore, to make the evaluation of dermal lymphocytes more objective, the authors counted them throughout the section. This was performed on a monitor attached to a video-camera viewing through a ·20 objective of attached microscope. Evaluation of biopsy specimen was blind and the evaluator was not aware of the clinical classification of the cases. The histological findings were then correlated with the clinical picture in each case. Statistical analysis was performed by Fisher exact test and Pearson x2 test using IBM SPSS statistics v21.0.
RESULTS
The choice of macule for biopsy depended on the nature of vitiligo. In case of stable vitiligo, margin of a representative macule was selected for biopsy. In case of unstable vitiligo, a macule which was either increasing in size or had newly appeared within 1 year of clinical presentation was selected. If more than one macules had appeared in the past year, then the most recent onset macule was selected. If the 2 conditions existed simultaneously, ie, some macule had been increasing in size and some had newly appeared within past 1 year, then most recent onset macule of appropriate size was selected for biopsy.
The study included 66 patients. Of the 66 patients, 29 were female (43.94%) and 37 were males (56.06%). M:F ratio was 1.3:1. There were 30 patients in stable vitiligo (Fig. 1A) group which included 16 males and 14 females. The unstable vitiligo (Fig. 1B) group consisted of 36 patients among whom there were 21 males and 15 females. The 2 groups were compared by Fisher exact test (P-value = 0.804). Thus, there is no significant difference between number of male and female patients in either of the groups. The patient’s age at presentation ranged from 7 to 56 years. Most patients (n = 26) were in the age group 17–26 years (39.4%). On comparing the age-distribution in the 2 groups, the most common age group at presentation was same in both groups, ie, 17–26 years. The most common age group at onset was 3–13 years and the least common was 43–53 years. Patients were further divided into stable and unstable groups based on their age group. The most common age group at onset in stable vitiligo group was 13–23 years, whereas that of unstable vitiligo group was 23–33 years. The age of onset was not found to be significantly associated with disease activity (P-value = 0.328). The mean duration between onset and presentation, in the 2 groups was analyzed. The mean 6 2 SD duration in unstable vitiligo group was 6.7 6 5.4 years, as compared with 11.8 6 8.2 years, in the stable group. This difference was statistically significant (P-value = 0.005). This implies that vitiligo shows trend toward instability with shorter duration between age of onset and presentation. The most common site of onset was legs (n = 26) followed by face (n = 22). Site of onset in the stable and unstable groups was further examined. The site of onset of vitiligo which was significantly and consistently associated with stability came out to be trunk and that associated with unstable group was hands (x2 test, P-value = 0.007). Positive family history of vitiligo was present in 9 (13.6%) patients of a total
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1. Margin of the representative lesion (totally inside the macule). 2. Perilesional area, which was taken to be roughly within 5 cm from the margin of the lesion. 3. Normal skin taken more than 5 cm away from the lesion margin.
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Clinicopathologic Analysis of Vitiligo
FIGURE 1. Clinical picture of vitiligo cases (A) stable vitiligo (B) unstable vitiligo.
66 patients. Family history was not significantly associated with disease activity (Fisher exact test, P-value = 0.721). Repigmentation of vitiligo macules was noticed in both the groups, ie, stable and unstable vitiligo. It was not found to be a significant predictor of disease stability (Fisher exact test, P-value = 0.059). Regression in size of the existing vitiligo macules, was seen in 16 patients, ie, almost half of stable cases (53.3%), and only in 8 patients (22.2%) of unstable vitiligo. The association of regression of lesions with stable disease was statistically significant (Fisher exact test, P-value = 0.011). In
unstable cases, wherever some lesions showed regression, simultaneous increase in size of other lesions and/or occurrence of new lesions was also noticed. Increase in the size of preexisting lesions in the unstable vitiligo group was present in 34 (94.4%) patients, whereas it was absent in all the patients of stable vitiligo group. New onset lesions were seen in 27 (75%) of 36 unstable vitiligo cases and none in stable cases. Biopsies were taken from 3 sites, ie, lesional, perilesional, and normal skin. The histopathological analysis was perfomed by a pathologist who was not aware of the clinical
FIGURE 2. Histopathological variables evaluated (A) spongiosis, (B) epidermal lymphocytosis, (C) basal cell vacuolation, (D) dermal lymphocytes. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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features. The histological parameters that were observed in each case were spongiosis (Fig. 2A), epidermal lymphocytes (Fig. 2B), and basal layer vacuolization (Fig. 2C) in the epidermis and dermal lymphocytes (Fig. 2D) along with melanophages in the dermis. While evaluating dermal lymphocytes, the cases were divided into 2 subcategories, ie, those with ,100 and .100 dermal lymphocytes. The results are summarized in Table 1. In the lesional skin, all the 5 histological variables were more frequently associated with clinically active disease. It was observed that the presence of spongiosis (P-value = 0.001), epidermal lymphocytes (P-value = 0.001), basal layer vacuolization (P-value = 0.033), and presence of more than 100 dermal lymphocytes (P-value , 0.0001) were individually significantly associated with unstable vitiligo suggesting them to be important histological predictors of disease activity. Histological examination of biopsy from perilesional area showed similar findings as those observed in lesional skin. All the findings were more common in unstable cases. Of these, the presence of spongiosis (P-value = 0.005), epidermal lymphocytes (P-value = 0.017), and more than 100 dermal lymphocytes (P-value = 0.002) were significantly associated with disease activity. The normal appearing skin in none of the 66 patients of vitiligo showed any of the abovementioned findings. However, few dermal lymphocytes were seen in all of them, which was always ,100 in each case. Although, the statistical analysis does point toward certain histological features which point toward stability or vice-versa but their assessment is subjective. Thus, these may not be helpful in routine histopathological reporting. Thus, to bring more objectivity into the histological assessment of these cases, all the 5 histological parameters were scored using a scoring system as shown in Table 2. The results of the scoring were then correlated with the clinical categorization. This correlation is shown in Table 3.
DISCUSSION Vitiligo is an enigmatic disease with varied clinical presentations and an unpredictable course. The basic defect is loss of functional melanocytes. However, the exact reasons for this are not entirely understood. The various theories that have been suggested, include cell mediated autoimmunity,13 humoral immunity,14 altered cellular metabolism,15 and melanocytorrhagy.16,17 The diagnosis of vitiligo is primarily based on clinical examination. However, other causes of hypopigmentation such as pityriasis alba, eczema or hypopigmented
mycosis fungoides should be confidently ruled out. These act as potential caveats in the diagnosis of vitiligo. In cases where there is uncertainty on clinical examination, a clinicopathological correlation is extremely important. The treatment outcome in vitiligo remains unpredictable too, more so, of nonsurgical approach. Surgical modalities may have negative outcomes, if patient selection is not performed properly. Till date, there is no single reliable tool that can consistently predict stability or activity of this disorder. However, this knowledge is of utmost importance in selection of the treatment modality, predicting treatment outcome and explaining prognosis to the patients. Many attempts in this context have been made in the past. There are a variety of methods suggested for this by different workers which include, absence of new lesion by history, no extension of old lesions, experimentally-induced koebnerization,7 vitiligo disease activity scoring,5 test minigrafting,6 biochemical parameters,18 ie, catecholamines level, antioxidants status, serum homocysteine levels, serological parameters, histopathology,9 and immunohistochemistry.12 Most of these, especially biochemical and serological parameters are cumbersome, unavailable, confined to research laboratories, and without any well-defined cut-off levels. The minigrafting test and experimentally induced koebnerization are invasive, not feasible, and inconsistent. This study was undertaken to evaluate the histopathological features of stable and unstable vitiligo. The objective was to come up with a reliable and systematic histopathological approach to solve this clinically-crucial diagnostic dilemma. The most accepted definition of stable vitiligo among many authorities remains as minimum one year of inactivity.19 Based on this history, 2 groups were formed, ie, stable and unstable vitiligo groups. Other parameters from history were studied to find significance of their association with stability. The sex and age of onset did not help in predicting activity of vitiligo, nor does the age at presentation. These findings are in concordance with the study by Hann et al,20 as they also reported that sex and age of onset don’t reliably differentiate progressive from nonprogressive vitligo. A negative family history was not found to be significantly associated with stability. This is in contrast to the study by Pajvani et al,21 in which a negative family history was significantly associated with regressive course of vitiligo. Trunk was significantly associated with stable vitiligo and hand was significantly related to unstable vitiligo. This finding can be explained on the basis of koebner phenomena because hands are the most trauma-prone site of body. This
TABLE 1. Summary of Histological Findings in Stable and Unstable Vitiligo Groups Stable Vitiligo S. No.
Histopathological Feature
1. 2. 3. 4. 5. 6.
Spongiosis Epidermal lymphocytes Basal vacuolization Dermal lymphocyte (.100) Dermal lymphocyte (,100) Melanophages
4
Lesional n (%) 1 1 1 1 29 2
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(3.3%) (3.3) (3.3) (3.3) (96.7) (6.6)
Unstable Vitiligo
Perilesional n (%)
Normal n (%)
1 (3.3) 2 (6.6) Nil 1 (3.3) 29 (96.7) 1 (3.3)
Nil Nil Nil Nil 30 (100) Nil
Lesional n (%) 13 13 7 21 15 3
(36.1) (36.1) (19.4) (58.3) (41.7) (8.3)
Perilesional n (%) 10 10 2 14 22 2
(27.7) (27.7) (5.5) (38.9) (61.1) (5.5)
Normal n (%) Nil Nil Nil Nil 36 (100) Nil
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Clinicopathologic Analysis of Vitiligo
TABLE 2. Proposed Vitiligo Histological Scoring System S. No.
Histological Feature
1.
Spongiosis
2.
Epidermal lymphocytes
3.
Basal vacuolization
4.
Dermal lymphocytes .100
5.
Melanophages
Observation
Score
Present Absent Present Absent Present Absent Present Absent Present Absent
1 0 1 0 1 0 1 0 1 0
may lead to constant presence of trigger, resulting in activity of vitiligo for longer duration than at other sites of body. There is very few data available on histopathological changes in the 2 groups of vitiligo. Therefore, there are no firm histopathological criteria on which this distinction can be made with a reasonable degree of certainty. There are few reports of inflammatory elements in the marginal skin of patients with vitiligo.11 These changes consist of focal epidermal and follicular inflammatory cell infiltration, superficial dermal perivascular and perifollicular mononuclear infiltrate. These changes are more avidly seen in unstable vitiligo as compared with stable disease. In this study, similar histopathological changes were studied and correlated with disease activity by history and clinical examination. In both, lesional and perilesional skin biopsies, epidermal changes, ie, spongiosis and presence of epidermal lymphocytes were significantly associated with disease activity as evident by history. Similarly, dermal infiltration was also significantly associated with active vitiligo in the biopsy specimens of both the areas. Basal layer vacuolization was significantly higher in unstable vitiligo group in lesional biopsies but not in perilesional ones. The above findings are in concordance with the study by Sharquie et al.11 The role of immunohistochemistry in vitiligo has been examined by few studies in the past. These studies have primarily focused on the characterization of inflammatory infiltrate in vitiligo. Badri et al10 showed an increase of CD3, CD4 and CD8 positive T cells in cases of vitiligo. Their findings suggest that T cells mediate the autoimmune destruction of melanocytes in vitiligo. In an another study, Ahn TABLE 3. Correlation of Proposed Vitiligo Histological Scoring System With Stable and Unstable Vitiligo S. No. 1. 2. 3. 4. 5. 6.
Total Score
Stable Vitiligo n (%)
5 4 3 2 1 0
Nil Nil 1 (2.8) 4 (11.1) 7 (19.4) 24 (66.7)
Unstable Vitiligo n (%) 3 3 8 10 6
Nil (10) (10) (26.7) (33) (20)
Confidence Interval 1.5 2 6 8.5 15
Nil 6 4.1 6 1.9 6 2.2 6 1.5 6 6.4
P-value = 0.4.
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et al12 examined the marginal skin of unstable and stable vitiligo using ICAM-1, HLA-DR, CD4, and CD8 monoclonal antibodies. ICAM-1 expression in epidermis was seen only in unstable group, whereas dermal ICAM-1 was expressed in both the groups. HLA-DR epidermal and dermal expression was seen in both groups. CD4 lymphocytes were expressed more strongly in unstable group. However, no difference in CD8 lymphocytes was seen in the 2 groups. Le Poole et al22 studied the inflammatory infiltrate within perilesional skin of 3 cases of unstable vitiligo. They found that epidermis-infiltrating T cells exhibit an increased CD8/CD4 ratio and increased cutaneous lymphocyte antigen and interleukin-2 receptor expression. In perilesional dermis, CD68 + OKM5-macrophages were more numerous than in lesional or nonlesional skin. Wankowicz-Kalinska et al23 showed that CD4 and CD8 positive lymphocytes immunopolarized to type 1. They hypothesized that this may be related to the melanocyte loss seen in vitiligo. However, these previous observations by various authors do not permit differentiation between stable and unstable vitiligo because they are a result as opposed to the cause of the disease process. They also did not compare the results with cases of stable vitiligo. Thus, it can be concluded from previous studies that immunohistochemistry is unlikely to play a decisive role in the distinction between stable and unstable vitiligo. A conclusive diagnosis is more likely to be reached by correlating histomorphological findings with clinical features. Thus, the histological features were then correlated with clinical findings. On correlating with the type of margin, it was seen that spongiosis, lymphocytes, basal cell vacuolization in the epidermis, and increased dermal lymphocytes when present were strongly associated with an ill defined margin. This is in agreement with the work of Benzekri et al9 who have hypothesized that hypomelanotic vitiligo lesions with poorly defined borders could be the clinical expression of histological features found at the margin like spongiosis, basal layer vacuolization, and dermal infiltrates. However, vitiligo lesions with sharply demarcated borders are related to absence of these histologic changes. Based on the observations in this study, the authors propose a histological scoring system as shown in Table 2. Each parameter is scored in every case and a total score is obtained. The minimum score possible is 0 and maximum is 5. On applying the histological scoring system, the results obtained in the 2 groups are summarized in Table 3. As can be seen, there is a definite overlap in the histological findings in the 2 groups. However, certain conclusions can be drawn. Cases of stable vitiligo tend to have a lower score and those of unstable vitiligo a higher score. Based on the findings of the correlation of histological score with clinical features, the authors recommend that every case of vitiligo should be scored on these parameters. The final scores and their corresponding recommended diagnosis are presented in Table 4. It is hoped that the adoption of a systematic reporting of these cases will bring more consistency and objectivity in their diagnosis. This will help us to more reliably and confidently manage these patients. Thus to conclude, distinction between stable and unstable vitiligo is of crucial importance in the management www.amjdermatopathology.com |
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TABLE 4. Final Recommended Diagnosis on the Basis of Score S. No.
Total Score
1. 2. 3.
5 4 3
4.
2
5.
0–1
Recommended Diagnosis Unstable vitiligo Unstable vitiligo Favor unstable vitiligo, however, clinical correlation is essential Favor stable vitiligo, however, clinical correlation is essential Strongly favor stable vitiligo, however, clinical correlation is essential
of this condition. To achieve this, many attempts have been made in the past using a variety of methods. The role of histopathology in this direction is not entirely established. The authors have shown that using certain histological features and correlating them with clinical features, a diagnosis can be made in most cases. A novel histological scoring system along with recommended diagnostic categories has been proposed. It is sincerely hoped that this will bring objectivity and consistency in the diagnosis of these patients. REFERENCES 1. Halder RM, Taliaferro SJ. Vitiligo. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hills publications; 2008:616–619. 2. Handa S, Kaur I. Vitiligo: clinical findings in 1436 patients. J Dermatol. 1999;26:653–657. 3. Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes. 2003;1:58. 4. Lahiri K. Stability in vitiligo—whats that? J Cutan Aesthet Surg. 2009;2: 38–40. 5. Parsad D, Gupta S. Standard guidelines of care for vitiligo surgery. Indian J Dermatol Venereol Leprol. 2008;74:37–45. 6. Falabella R. Surgical treatment of vitiligo: why, when and how. J Eur Acad Dermatol Venereol. 2003;17:518–520. 7. Njoo MD, Das PK, Bos JD, et al. Association of the Koebners phenomena with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol. 1999;135:414.
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8. Falabella R, Arrunategui A, Barona MI, et al. The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation. J Am Acad Dermatol. 1995;32:228–232. 9. Benzekri L, Gauthier Y, Hamada S, et al. Clinical features and histological findings are potential indicators of activity in lesions of common vitiligo. Br J Dermatol. 2013;168:265–271. 10. Badri AM, Todd PM, Garioch JJ, et al. An immunohistological study of cutaneous lymphocytes in vitiligo. J Pathol. 1993;170:149–155. 11. Sharquie KE, Mehenna SH, Naji AA, et al. Inflammatory changes in vitiligo stage I and stage II depigmentation. Am J Dermatopathol. 2004;26:108–112. 12. Ahn SK, Choi EH, Lee SH, et al. Immunohistochemical studies from vitiligo: comparison between active and inactive lesions. Yonsei Med J. 1994;35:404–410. 13. van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, et al. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest. 2000;80:1299–1309. 14. Cui J, Arita Y, Bystryn JC. Cytolytic antibodies to melanocytes in vitiligo. J Invest Dermatol. 1993;100:812–815. 15. Dell’anna ML, Picardo M. A review and a new hypothesis for nonimmunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;19:406–411. 16. Gauthier Y, Cario Andre M, Taïeb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy? Pigment Cell Res. 2003;16:322–332. 17. Kumar R, Parsad D, Kanwar AJ. Role of apoptosis and melanocytorrhagy: a comparative study of melanocyte adhesion in stable and unstable vitiligo. Br J Dermatol. 2011;164:187–191. 18. Rao A, Gupta S, Dinda AK, et al. Study of clinical, biochemical and immunological factors determining stability of disease in patients with generalized vitiligo undergoing melanocyte transplantation. Br J Dermatol. 2012;166:1230–1236. 19. Yaghoobi R, Omidian M, Bagherani N. Vitiligo: a review of the published work. J Dermatol. 2011;38:419–431. 20. Hann SK, Chun WH, Park YK. Clinical characteristics of progressive vitiligo. Int J Dermatol. 1997;36:353–355. 21. Pajvani U, Ahmad N, Wiley A, et al. The relationship between family medical history and childhood vitiligo. J Am Acad Dermatol. 2006;55: 238–244. 22. Le Poole IC, van den Wijngaard RM, Westerhof W, et al. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol. 1996;148:1219–1228. 23. Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, et al. Immunopolarization of CD4+ and CD8+ T cells to Type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest. 2003;83:683–695.
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