Original Paper Received: April 16, 2014 Accepted after revision: September 19, 2014 Published online: January 28, 2015
Dermatology 2015;230:143–149 DOI: 10.1159/000368772
Concomitant Mycosis Fungoides and Vitiligo: How Mycosis Fungoides May Contribute to Melanocyte Destruction Jennifer L. Herrmann a Erica Syklawer b Madeline Tarrillion c Madeleine Duvic b Lauren C. Hughey a
a
Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala., b Department of Dermatology, University of Texas MD Anderson Cancer Center, and c Department of Pathology, University of Texas at Houston, Houston, Tex., USA
Abstract Background: Few reports have described vitiligo developing in patients with cutaneous T-cell lymphoma (CTCL). Objective: We sought to identify possible factors that might predispose patients with CTCL to vitiligo. Methods: Patient demographics, CTCL disease characteristics and treatments were analyzed in 25 patients with CTCL who developed vitiligo. Cox proportional hazards modeling was used to identify associations of risk factors with the development of vitiligo. Results: Younger age, later CTCL disease stage (stages IIB–IV) and presence of a CD8+CD4– mycosis fungoides phenotype were associated with the development of vitiligo. After adjusting for disease stage, increased risk of vitiligo was associated with methotrexate and CD4 antibody therapies (although the total number of patients with these was small), while decreased risk was associated with nitrogen mustard and PUVA therapies. Conclusions: No single feature was common to all of our patients, suggesting that multiple factors may contribute to the development of vitiligo in a patient-specific fashion. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1018–8665/15/2302–0143$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of neoplastic disorders defined by a primary accumulation of malignant memory T cells that home to the skin [1, 2]. The most common clinical form of CTCL is mycosis fungoides (MF), characterized by erythematous patches, scaling plaques and tumors distributed preferentially over sun-protected skin surfaces [3, 4]. Vitiligo is characterized by the destruction of epidermal melanocytes. Although its etiology is poorly understood, the most widely accepted theory of pathogenesis involves autoimmunity whereby a T cell-mediated process contributes to melanocyte destruction [5]. The worldwide incidence of vitiligo is estimated at between 0.5 and 2% [6], while the incidence of MF is approximately 0.4 in 100,000 [7]. Given the rarity of MF, it is difficult to accurately estimate the incidence of vitiligo in patients with MF. However, anecdotal evidence from experts at several CTCL centers across the United States supports that vitiligo occurs more frequently in those with MF than by chance alone, and it is likely that concomitant disease occurrence is underreported. Very few cases of vitiligo developing in patients with CTCL have been cited in the literature [8–11], and of these, vitiligo Dr. Jennifer Herrmann University of Alabama at Birmingham 1530 3rd Ave. South, EFH 414 Birmingham, AL 35294 (USA) E-Mail dr.jenniferherrmann @ gmail.com
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Key Words Cutaneous T-cell lymphoma · Cytokines · Leukoderma · Lymphoma · Mycosis fungoides · Vitiligo
a
Color version available online
has been associated with either a particular CTCL disease state, such as an MF flare or Sézary syndrome, or specific CTCL treatments, including PUVA or interferon alpha (IFNα) therapy. Given that immune system deregulation has been implicated in both diseases, it is conceivable that dysfunction of the aberrant T cells in CTCL may predispose patients to T cell-mediated destruction of melanocytes. Whether it is the malignant clone itself inducing a cytotoxic effect, a CTCL-provoked altered signaling milieu, CTCL treatment or some other factor that contributes to loss of melanocytes remains unknown. To better understand the association between MF and vitiligo, we analyzed the cases of 25 patients with CTCL who developed vitiligo.
b
c
Methods
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d
Fig. 1. Clinical and histopathological vitiligo. a, b Vitiligo involving the distal lower extremities (a) and dorsal hand (b) in patient 1. c Biopsy of a depigmented macule showing complete loss of basal layer melanin. d MART-1 stain demonstrated complete absence of epidermal melanocytes when compared to appropriate reactive controls.
and frequency tabulation. Given that this was a time-to-event study (diagnosis of CTCL to development of vitiligo for the subject group and diagnosis of CTCL to the current date for controls), the Cox proportional hazards model was used to determine associations of risk factors with development of vitiligo. Disease stages were grouped into early and late categories, defined as stages IA– IIA and stages IIB–IVB, respectively, to increase the number of data points in each category. All medications were adjusted for early versus late disease stage as patients with more advanced disease are typically treated with more systemic and greater numbers of medications. Statistical significance was claimed at p < 0.05. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, N.C., USA).
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CTCL databases from two academic centers with CTCL specialty clinics were queried for concomitant diagnoses of CTCL and vitiligo. Of 2,350 searched patient records, we identified 27 patients with both diagnoses. Two patients with vitiligo diagnoses preceding those of CTCL were excluded. Diagnoses of CTCL were made by clinical evaluation, confirmatory biopsy (reviewed by a board-certified dermatopathologist) and positive gene rearrangement studies when performed. All diagnoses of vitiligo were made clinically, where individual lesions were required to be chalkwhite macules and patches with mostly discrete convex margins in classic distributions, including generalized vitiligo vulgaris, acrofacial or generalized mixed vitiligo. All diagnoses were confirmed by fluorescence under Wood’s lamp illumination, and in 7 cases verified by biopsy. Complete absence of melanocytes was confirmed by MART-1 staining in these 7 biopsied cases. The remaining cases were not biopsied as clinical appearance/Wood’s lamp illumination strongly supported the diagnoses of vitiligo. Diagnoses other than vitiligo cannot completely be excluded in patients without biopsies. After thorough chart review, patient demographics, immunohistochemistry of CTCL infiltrates, time from CTCL diagnosis to vitiligo diagnosis, location of vitiligo patches in relation to CTCL patches or plaques, treatment regimens prior to the development of vitiligo, personal and family history of autoimmune disease, Tumor Node Metastasis Blood (TNMB) classifications and CTCL disease stages were recorded. TNMB/disease stages were based on the 2007 staging guidelines defined by the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organisation for Research and Treatment of Cancer (EORTC) [12]. To identify possible predictors of vitiligo in the setting of CTCL, 50 additional control patients with only CTCL diagnoses were selected at random from both institutions. Diagnoses were confirmed as above and patient demographics, CTCL disease features and treatment modalities were similarly determined in this cohort. Statistical analysis and model building were performed on patients who developed vitiligo. Baseline demographic variables and CTCL clinical data were analyzed using descriptive statistics
Table 1. Summary of disease characteristics and treatment regimens Age/ ethnicity or race/ sex
Immunohistochemical profile of MF infiltrate
TNMB at diagnosis of MF
Disease stage at referral to our clinic1
Disease Time3 TNMB at diagnosis stage of vitiligo early vs. later2
Loca- MF medications prior to tion4 vitiligo diagnosis
56/Bl/M
CD4+CD8–
T2N1M0B0
IIA
E
36
T0N0M0B0
B
72/Bl/F 52/H/F
CD8+ CD4+CD8–CD25+
T2N0M0B0 T2N0M0B0
IB IB
E E
7 108
T2N0M0B0 T2N0M0B0
N
59/W/M
CD4+CD8–CD25+
T2N0M0B0
IB
E
9
T2N0M0B0
P
44/Bl/F 52/W/F 69/H/F 61/W/F 31/H/F 33/H/M 40/H/M
CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8–CD25+ CD4+CD8–
T3N1M0B1 T1N0M0B0 T1N0M0B0 T4N1M0B0 T2N0M0B0 T2N0M0B0 T4N1M1B2
L E E L E E L
84 48
T4N1M0B2 T1N0M0B0 T1N0M0B0 T1N0M0B1 T2N0M0B0 T2N0M0B0 T4N0M0B1
B B P N P P
43/Bl/F 68/W/F 17/W/F 77/W/M 56/Bl/M 62/W/M
CD4+CD8– CD8+CD4– CD8+CD4– CD4+CD8– CD4+CD8–CD25+ CD4+CD8–
T2N0M0B0 T1N0M0B0 T1N0M0B0 T4N3M1B2 T3N1M0B1 T4N1M0B2
IIB IA IA III IB IB IVB (LCT, SS) IB IA IA IVB (SS) IIB (LCT) IVA (SS)
E E E L L L
144 24 4 12 36 144
T2N0M0B0 T1N0M0B0 T1N0M0B0 T2N1M0B2 T3N0M0B0 T2N0M0B2
P P P P P P
71/Bl/F 79/H/F 62/W/M 72/W/M
CD4+CD8–CD25+ CD4+CD8–CD25+ CD4+CD8– CD4+CD8–
T1N1M0B1 T2N0M0B1 T4N0M0B0 T3N0M0B0
IIA IB III IIB
E E L L
12 1 12 240
T1N1M0B1 T2N0M0B1 T2N0M0B0 T2N0M0B0
B P B N
81/Bl/F 42/W/F 49/Bl/F
CD4+CD8– CD4+CD8– CD4+CD8–
T2N0M0B0 T1N0M0B0 T2N0M0B0
IB IA IIA
E E E
192 12 72
T1N0M0B0 T1N0M0B0 T2N0M0B0
B N B
67/W/M
CD4+CD8–
T3N0M0B0
IIB
L
9
T1N0M0B0
B
Ab = Antibody; AT = acitretin; B = both in sites and not in sites of MF patches or plaques; Bl = black; DD = denileukin diftitox; F = female; H = Hispanic; HDACi = histone deacetylase inhibitor; HT = hypothyroidism independent of oral bexarotene therapy; Iso = isotretinoin; LCT = large-cell transformation of MF; M = male; MTX = methotrexate; N = not in sites of MF patches or plaques; nbUVB = narrow-band UVB; NM = nitrogen mustard; OB = oral bexarotene; OC = oral corticosteroid; OTC = other traditional chemotherapy; P = in sites of MF patches or plaques; PP = photophoresis; SS = Sézary syndrome; TB = topical bexarotene; TCS = topical corticosteroid; TEBT = total electron beam therapy; W = white. 1 TNMB classifications
Results
We describe 25 cases of vitiligo which developed in 11 male and 14 female patients with CTCL, occurring 3 months to several years after their initial CTCL diagnoses (table 1, fig. 1). Our patients represented a diverse population with Fitzpatrick skin types I–V, ages ranging from 17 to 81 years, and disease stages spanning from IA to IVB at the time of referral to each institution. TNMB classifiMycosis Fungoides and Vitiligo
Family autoimmune disease
TCS, OB, PUVA, IFNα, DD, yes (HT) HDACi TCS, NM TCS, NM, TB, OB, Iso, nbUVB, IFNα TCS, OC, IFNα yes (vitiligo) TCS, OB, MTX, TEBT, OC TCS, TB, nbUVB yes (HT) TCS, NM TCS, OC, OB, PUVA, IFNα TCS, OC TCS TCS, TB, OB, IFNα, PP, DD yes (HT) TCS nbUVB TCS TCS, NM, OB, IFNα, PP TCS, OTC, AT, Iso, MTX, DD TCS, NM, TB, OB, PUVA, IFNα, TEBT, PP, OTC TEBT, local radiation TCS TCS, AT, nbUVB TCS, NM, IFNα, nbUVB, TEBT, local radiation TCS, NM, OB, Iso, MTX TCS, TB, OB TCS, TB, OB, MTX, IFNα, CD4 Ab TCS, OB, MTX, PUVA, nbUVB, HDACi
and disease stages were based on the 2007 staging guidelines defined by the ISCL and the cutaneous lymphoma task force of the EORTC [12]. T1: 10% BSA affected; T3: + tumors; T4: + erythroderma; N0: no nodal involvement; N1 – 3: + nodal involvement; M0: no metastases; M1: + metastases; B0: 5% Sézary cells, but not meeting Sézary syndrome criteria; B2: Sézary syndrome. 2 E = Early (stages IA, IB, IIA) and L = later (stage IIB or greater). 3 Time from MF diagnosis to vitiligo diagnosis (months). 4 Location of vitiligo patches in relation to MF patches/plaques. * The patient had concomitant diagnoses of CTCL and vitiligo.
cation at the time of initial CTCL diagnosis and time at which patients developed vitiligo did not suggest that vitiligo was associated with MF progression or Sézary syndrome. Only one patient showed TNMB progression while 7 showed improvement and the remaining 17 had no change in classification. Vitiliginous macules and patches occurred in skin clinically ‘clear’ of MF patches and plaques in only 4 patients, whereas they occurred only in areas of MF involvement (11 patients) or areas of Dermatology 2015;230:143–149 DOI: 10.1159/000368772
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24 0* 12 24
Personal autoimmune disease
Age (per year) CTCL clone phenotype CD4+CD8– (reference) CD8+CD4– CTCL disease stage Early (IA, IB, IIA) (reference) Late (IIB, III, IVA, IVB) Methotrexate No (reference) Yes CD4 antibody No (reference) Yes Topical nitrogen mustard No (reference) Yes PUVA No (reference) Yes
Hazard ratio
p
0.973
0.0334
12.6
0.0001
2.3
0.0482
3.86
0.0178
5.43
0.0282
0.33
0.0220
0.31
0.0339
Color version available online
Table 2. Results of Cox proportional hazards modeling for development of vitiligo
a
b
Medications were adjusted for disease stage.
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Fig. 2. Vitiligo under Wood’s lamp illumination. Vitiligo involving the axilla clinically (a) fluoresces bright white under Wood’s lamp illumination (b). Hypopigmented MF lacks this fluorescent char-
acter (not shown).
Discussion
Vitiligo is characterized by the progressive destruction of melanocytes, resulting in depigmented macules and patches [5]. Although post-inflammatory hypopigmentation and hypopigmented MF can be confused with vitiligo clinically, the combination of patient demographics, appearance of all patients’ lesions under Wood’s lamp illumination and biopsy results supported diagnoses of vitiligo in our patients (fig. 2). Post-inflammatory hypopigmentation is characterized by hypopigmented patches that do not fluoresce brightly under Wood’s lamp illumination, and biopsy shows presence of melanocytes along with dermal melanophages [13]. Hypopigmented MF typically occurs in young, darker-skinned patients with histology revealing features of MF and preservation of melanocytes [14]. The clinical morphologies and distriHerrmann /Syklawer /Tarrillion /Duvic / Hughey
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both MF-involved and MF-uninvolved skin (8 patients). In all 7 cases where vitiligo was biopsied, no evidence of MF was identified in the depigmented skin specimen. Immunohistochemical analyses of MF lesions identified that malignant infiltrates were CD4+CD8– in most cases, but 3 patients had CD8+CD4– MF phenotypes. Finally, our cohort underwent diverse treatment regimens, including differing combinations of topical, systemic and/or lightbased therapies prior to their diagnoses of vitiligo. The results of Cox proportional hazards modeling of possible risk factors for developing vitiligo in the setting of CTCL are summarized in table 2. Younger age (HR: 0.97 [3% decreased risk per year]), late-stage disease (HR: 2.30), and CD8+CD4– MF phenotype (HR: 12.6) were factors associated with increased risk of vitiligo, although only 3 total patients had CD8+CD4– MF phenotypes. When medications were adjusted for disease stage (early versus late), methotrexate (HR: 3.8) and CD4 antibody (HR: 5.43) were associated with increased risk of developing vitiligo, while nitrogen mustard (HR: 0.33) and PUVA (HR: 0.31) showed decreased risk. The total number of patients treated with each of these modalities was low: 5 and 2 patients had been on methotrexate and CD4 antibody, respectively.
tumor cells directed against melanocyte antigens or from autoantibodies such as antityrosinase. In a more recent study that examined cutaneous lymphocytes in one patient with Sézary syndrome who developed vitiligo, vitiligo was found to be related to the presence of CD8+ T lymphocytes specific for melanocyte differentiation antigens melan-A/MART-1 and to a lesser extent tyrosinase and gp100 [11]. This may be similar to melanoma-associated depigmentation that develops in melanoma, which is thought to result from a CD8+ cytotoxic reaction against melanoma tumor cells [25]. Other studies have associated therapeutic agents, including treatment with PUVA and IFNα, with vitiligo in CTCL patients [9–11, 22, 26, 27]. Considering these reports collectively, it becomes evident that multiple factors have been implicated in the development of vitiligo in patients with CTCL. In our cohort of 25 patients, younger age, later disease stage and presence of CD8+CD4– malignant clones, although only three total patients carried this phenotype, were associated with the development of vitiligo. In patients with CD8+CD4– phenotypes, a malignant T cell clone with cytotoxic properties may have contributed to melanocyte destruction, as CD8+ malignant infiltrates have been identified in some patients with CTCL who developed vitiligo [28]. A derangement in CD4+ cells may have also generated an immune environment permissive for vitiligo. Multiple studies have suggested that in both early-stage CTCL [29] as well as in patients with later-stage disease undergoing treatment [30], a T-helper immune response dominates, and T-helper cytokines have also been identified in patients with vitiligo [31]. Although we did not investigate specific signaling molecules directly, it is possible that the pro-inflammatory cytokine IL-17 plays a role, as higher levels of IL-17 have been documented in both patients with MF [32, 33] and vitiligo [34]. IL-17 signaling promotes an inflammatory environment that could play a role in vitiligo by increasing levels of reactive oxygen species. Finally, it also may be that a CTCL-induced alteration of regulatory T cells (Tregs) is related to the development of vitiligo. Several studies have suggested that early MF lesions harbor benign Tregs that help suppress malignant expansion, while more advanced disease stages show a paucity of Tregs [35]. In other reports the malignant T cells in some patients with Sézary syndrome have been shown to display Treg phenotypes themselves [35]. Since Tregs are crucial for maintaining peripheral tolerance and preventing inappropriate excessive immune reactions, it is possible that CTCL-induced perturbations in
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bution of depigmented lesions in our cohort further supported diagnoses of vitiligo over more general leukoderma. All of our patients had chalk-white macules and patches with mostly discrete convex margins, and all developed classic patterns of lesion distribution, including generalized vitiligo vulgaris, acrofacial or generalized mixed vitiligo. Moreover, as is often associated with vitiligo, many patients suffered from progressive depigmentation, which occurred despite improvement or even clearance of MF patches and plaques. Finally, none of our cohort had diagnoses of vitiligo prior to their developing MF, excluding the possibility of simple koebnerization of MF lesions. Although the etiology of vitiligo remains obscure, several theories have explained depigmentation. The biochemical hypothesis argues that an accumulation of toxic metabolites from melanogenesis destroys melanocytes [15], while the neural hypothesis proposes melanocyte destruction by neurochemical toxic mediators [16]. The impaired redox status theory maintains that the breakdown of free radical defense and an excess of hydrogen peroxide contribute to melanocyte destruction [17], while the theory of melanocytorrhagy suggests that genetically defective melanocyte adhesion results in the disappearance of melanocytes [18]. The most widely accepted autoimmune theory implicates cellular and/or humoral immune mechanisms in melanocyte elimination [19, 20]. Although each of these hypotheses has corroborating evidence, none fully accounts for all cases of vitiligo. It is therefore possible that vitiligo represents a ‘syndrome’ rather than one disease, with numerous but not mutually exclusive pathways leading to melanocyte disappearance, where complex interactions of biochemical, environmental and immunological events operate on a permissive genetic background. It is possible that other cutaneous diseases which alter the skin’s biochemical and signaling milieu impact this pathogenic process. Indeed, the development of vitiligo has been reported in sites of previously active psoriasis and atopic dermatitis [21–24]. Although rare, vitiligo has also been documented in patients with CTCL. In 1987, Alcalay et al. [8] reported a case of biopsy-confirmed vitiligo in a gentleman with Sézary syndrome. They suggested that a dense dermal lymphocytic infiltrate composed mainly of helper T cells contributed to melanocyte destruction by stimulating a cell-mediated cytotoxic process. More than a decade later, Bouloc et al. [9] described four erythrodermic CTCL patients who developed vitiligo during disease flares. It was hypothesized that depigmentation resulted from the cytotoxic activity of reactive
Tregs, particularly those leading to their decrease, set the stage for or even perpetuate/accelerate autoimmunity. Indeed, recent reports have shown that some vitiligo patients have either drastically decreased numbers of Tregs in vitiliginous skin [36] or functionally defective Tregs in their peripheral blood [37]. In our cohort, treatment with either methotrexate or CD4 antibody was associated with increased risk of developing vitiligo; however, few patients were treated with these therapies, and it is uncertain whether these associations are generalizable. In theory, medication-induced inflammation and reactive oxygen species or altered epidermal signaling may have played a role in melanocyte destruction. Fewer patients treated with nitrogen mustard or PUVA developed vitiligo; however, again, the total numbers treated were small. Topical nitrogen mustard and PUVA therapy have both been used successfully to achieve repigmentation in vitiligo [38]. PUVA therapy induces lymphocyte apoptosis and stimulates melanogenesis, which may explain the decreased incidence of vitiligo in patients treated with this modality. Future studies might prospectively analyze the degree and distribution of vitiligo as it relates to medication types, their doses and their withdrawal. In summary, younger age, non-Caucasian white race, presence of CD8+CD4– malignant clones, later disease
stage and treatment with methotrexate or CD4 antibody were associated with the development of vitiligo in some patients of our limited cohort. No factor was common to all patients, and we believe that our patient diversity supports the growing knowledge of the complexity of the pathogenesis of vitiligo. Multiple factors likely contribute to melanocyte destruction in patients with CTCL who develop this disease. Variation may depend on the distinct CTCL malignant clone, treatment regimen and individual genetics. Vitiligo may be best considered a ‘complex trait’, involving multiple genes as well as non-genetic factors. As further research refines its etiology, we may better understand those aspects that are most relevant to its occurrence in patients with CTCL.
Acknowledgements We would like to thank Dr. Aleodor A. Andea and Dr. Zendee P. Elaba for their help with histopathological photographs, analysis and interpretation.
Disclosure Statement The authors declare no conflicts on interest. There were no funding sources.
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Dermatology 2015;230:143–149 DOI: 10.1159/000368772
Concomitant Mycosis Fungoides and Vitiligo: How Mycosis Fungoides May Contribute to Melanocyte Destruction Jennifer L. Herrmann a Erica Syklawer b Madeline Tarrillion c Madeleine Duvic b Lauren C. Hughey a
a
Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala., b Department of Dermatology, University of Texas MD Anderson Cancer Center, and c Department of Pathology, University of Texas at Houston, Houston, Tex., USA
Abstract Background: Few reports have described vitiligo developing in patients with cutaneous T-cell lymphoma (CTCL). Objective: We sought to identify possible factors that might predispose patients with CTCL to vitiligo. Methods: Patient demographics, CTCL disease characteristics and treatments were analyzed in 25 patients with CTCL who developed vitiligo. Cox proportional hazards modeling was used to identify associations of risk factors with the development of vitiligo. Results: Younger age, later CTCL disease stage (stages IIB–IV) and presence of a CD8+CD4– mycosis fungoides phenotype were associated with the development of vitiligo. After adjusting for disease stage, increased risk of vitiligo was associated with methotrexate and CD4 antibody therapies (although the total number of patients with these was small), while decreased risk was associated with nitrogen mustard and PUVA therapies. Conclusions: No single feature was common to all of our patients, suggesting that multiple factors may contribute to the development of vitiligo in a patient-specific fashion. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1018–8665/15/2302–0143$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of neoplastic disorders defined by a primary accumulation of malignant memory T cells that home to the skin [1, 2]. The most common clinical form of CTCL is mycosis fungoides (MF), characterized by erythematous patches, scaling plaques and tumors distributed preferentially over sun-protected skin surfaces [3, 4]. Vitiligo is characterized by the destruction of epidermal melanocytes. Although its etiology is poorly understood, the most widely accepted theory of pathogenesis involves autoimmunity whereby a T cell-mediated process contributes to melanocyte destruction [5]. The worldwide incidence of vitiligo is estimated at between 0.5 and 2% [6], while the incidence of MF is approximately 0.4 in 100,000 [7]. Given the rarity of MF, it is difficult to accurately estimate the incidence of vitiligo in patients with MF. However, anecdotal evidence from experts at several CTCL centers across the United States supports that vitiligo occurs more frequently in those with MF than by chance alone, and it is likely that concomitant disease occurrence is underreported. Very few cases of vitiligo developing in patients with CTCL have been cited in the literature [8–11], and of these, vitiligo Dr. Jennifer Herrmann University of Alabama at Birmingham 1530 3rd Ave. South, EFH 414 Birmingham, AL 35294 (USA) E-Mail dr.jenniferherrmann @ gmail.com
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Key Words Cutaneous T-cell lymphoma · Cytokines · Leukoderma · Lymphoma · Mycosis fungoides · Vitiligo
a
Color version available online
has been associated with either a particular CTCL disease state, such as an MF flare or Sézary syndrome, or specific CTCL treatments, including PUVA or interferon alpha (IFNα) therapy. Given that immune system deregulation has been implicated in both diseases, it is conceivable that dysfunction of the aberrant T cells in CTCL may predispose patients to T cell-mediated destruction of melanocytes. Whether it is the malignant clone itself inducing a cytotoxic effect, a CTCL-provoked altered signaling milieu, CTCL treatment or some other factor that contributes to loss of melanocytes remains unknown. To better understand the association between MF and vitiligo, we analyzed the cases of 25 patients with CTCL who developed vitiligo.
b
c
Methods
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d
Fig. 1. Clinical and histopathological vitiligo. a, b Vitiligo involving the distal lower extremities (a) and dorsal hand (b) in patient 1. c Biopsy of a depigmented macule showing complete loss of basal layer melanin. d MART-1 stain demonstrated complete absence of epidermal melanocytes when compared to appropriate reactive controls.
and frequency tabulation. Given that this was a time-to-event study (diagnosis of CTCL to development of vitiligo for the subject group and diagnosis of CTCL to the current date for controls), the Cox proportional hazards model was used to determine associations of risk factors with development of vitiligo. Disease stages were grouped into early and late categories, defined as stages IA– IIA and stages IIB–IVB, respectively, to increase the number of data points in each category. All medications were adjusted for early versus late disease stage as patients with more advanced disease are typically treated with more systemic and greater numbers of medications. Statistical significance was claimed at p < 0.05. Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, N.C., USA).
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CTCL databases from two academic centers with CTCL specialty clinics were queried for concomitant diagnoses of CTCL and vitiligo. Of 2,350 searched patient records, we identified 27 patients with both diagnoses. Two patients with vitiligo diagnoses preceding those of CTCL were excluded. Diagnoses of CTCL were made by clinical evaluation, confirmatory biopsy (reviewed by a board-certified dermatopathologist) and positive gene rearrangement studies when performed. All diagnoses of vitiligo were made clinically, where individual lesions were required to be chalkwhite macules and patches with mostly discrete convex margins in classic distributions, including generalized vitiligo vulgaris, acrofacial or generalized mixed vitiligo. All diagnoses were confirmed by fluorescence under Wood’s lamp illumination, and in 7 cases verified by biopsy. Complete absence of melanocytes was confirmed by MART-1 staining in these 7 biopsied cases. The remaining cases were not biopsied as clinical appearance/Wood’s lamp illumination strongly supported the diagnoses of vitiligo. Diagnoses other than vitiligo cannot completely be excluded in patients without biopsies. After thorough chart review, patient demographics, immunohistochemistry of CTCL infiltrates, time from CTCL diagnosis to vitiligo diagnosis, location of vitiligo patches in relation to CTCL patches or plaques, treatment regimens prior to the development of vitiligo, personal and family history of autoimmune disease, Tumor Node Metastasis Blood (TNMB) classifications and CTCL disease stages were recorded. TNMB/disease stages were based on the 2007 staging guidelines defined by the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organisation for Research and Treatment of Cancer (EORTC) [12]. To identify possible predictors of vitiligo in the setting of CTCL, 50 additional control patients with only CTCL diagnoses were selected at random from both institutions. Diagnoses were confirmed as above and patient demographics, CTCL disease features and treatment modalities were similarly determined in this cohort. Statistical analysis and model building were performed on patients who developed vitiligo. Baseline demographic variables and CTCL clinical data were analyzed using descriptive statistics
Table 1. Summary of disease characteristics and treatment regimens Age/ ethnicity or race/ sex
Immunohistochemical profile of MF infiltrate
TNMB at diagnosis of MF
Disease stage at referral to our clinic1
Disease Time3 TNMB at diagnosis stage of vitiligo early vs. later2
Loca- MF medications prior to tion4 vitiligo diagnosis
56/Bl/M
CD4+CD8–
T2N1M0B0
IIA
E
36
T0N0M0B0
B
72/Bl/F 52/H/F
CD8+ CD4+CD8–CD25+
T2N0M0B0 T2N0M0B0
IB IB
E E
7 108
T2N0M0B0 T2N0M0B0
N
59/W/M
CD4+CD8–CD25+
T2N0M0B0
IB
E
9
T2N0M0B0
P
44/Bl/F 52/W/F 69/H/F 61/W/F 31/H/F 33/H/M 40/H/M
CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8– CD4+CD8–CD25+ CD4+CD8–
T3N1M0B1 T1N0M0B0 T1N0M0B0 T4N1M0B0 T2N0M0B0 T2N0M0B0 T4N1M1B2
L E E L E E L
84 48
T4N1M0B2 T1N0M0B0 T1N0M0B0 T1N0M0B1 T2N0M0B0 T2N0M0B0 T4N0M0B1
B B P N P P
43/Bl/F 68/W/F 17/W/F 77/W/M 56/Bl/M 62/W/M
CD4+CD8– CD8+CD4– CD8+CD4– CD4+CD8– CD4+CD8–CD25+ CD4+CD8–
T2N0M0B0 T1N0M0B0 T1N0M0B0 T4N3M1B2 T3N1M0B1 T4N1M0B2
IIB IA IA III IB IB IVB (LCT, SS) IB IA IA IVB (SS) IIB (LCT) IVA (SS)
E E E L L L
144 24 4 12 36 144
T2N0M0B0 T1N0M0B0 T1N0M0B0 T2N1M0B2 T3N0M0B0 T2N0M0B2
P P P P P P
71/Bl/F 79/H/F 62/W/M 72/W/M
CD4+CD8–CD25+ CD4+CD8–CD25+ CD4+CD8– CD4+CD8–
T1N1M0B1 T2N0M0B1 T4N0M0B0 T3N0M0B0
IIA IB III IIB
E E L L
12 1 12 240
T1N1M0B1 T2N0M0B1 T2N0M0B0 T2N0M0B0
B P B N
81/Bl/F 42/W/F 49/Bl/F
CD4+CD8– CD4+CD8– CD4+CD8–
T2N0M0B0 T1N0M0B0 T2N0M0B0
IB IA IIA
E E E
192 12 72
T1N0M0B0 T1N0M0B0 T2N0M0B0
B N B
67/W/M
CD4+CD8–
T3N0M0B0
IIB
L
9
T1N0M0B0
B
Ab = Antibody; AT = acitretin; B = both in sites and not in sites of MF patches or plaques; Bl = black; DD = denileukin diftitox; F = female; H = Hispanic; HDACi = histone deacetylase inhibitor; HT = hypothyroidism independent of oral bexarotene therapy; Iso = isotretinoin; LCT = large-cell transformation of MF; M = male; MTX = methotrexate; N = not in sites of MF patches or plaques; nbUVB = narrow-band UVB; NM = nitrogen mustard; OB = oral bexarotene; OC = oral corticosteroid; OTC = other traditional chemotherapy; P = in sites of MF patches or plaques; PP = photophoresis; SS = Sézary syndrome; TB = topical bexarotene; TCS = topical corticosteroid; TEBT = total electron beam therapy; W = white. 1 TNMB classifications
Results
We describe 25 cases of vitiligo which developed in 11 male and 14 female patients with CTCL, occurring 3 months to several years after their initial CTCL diagnoses (table 1, fig. 1). Our patients represented a diverse population with Fitzpatrick skin types I–V, ages ranging from 17 to 81 years, and disease stages spanning from IA to IVB at the time of referral to each institution. TNMB classifiMycosis Fungoides and Vitiligo
Family autoimmune disease
TCS, OB, PUVA, IFNα, DD, yes (HT) HDACi TCS, NM TCS, NM, TB, OB, Iso, nbUVB, IFNα TCS, OC, IFNα yes (vitiligo) TCS, OB, MTX, TEBT, OC TCS, TB, nbUVB yes (HT) TCS, NM TCS, OC, OB, PUVA, IFNα TCS, OC TCS TCS, TB, OB, IFNα, PP, DD yes (HT) TCS nbUVB TCS TCS, NM, OB, IFNα, PP TCS, OTC, AT, Iso, MTX, DD TCS, NM, TB, OB, PUVA, IFNα, TEBT, PP, OTC TEBT, local radiation TCS TCS, AT, nbUVB TCS, NM, IFNα, nbUVB, TEBT, local radiation TCS, NM, OB, Iso, MTX TCS, TB, OB TCS, TB, OB, MTX, IFNα, CD4 Ab TCS, OB, MTX, PUVA, nbUVB, HDACi
and disease stages were based on the 2007 staging guidelines defined by the ISCL and the cutaneous lymphoma task force of the EORTC [12]. T1: 10% BSA affected; T3: + tumors; T4: + erythroderma; N0: no nodal involvement; N1 – 3: + nodal involvement; M0: no metastases; M1: + metastases; B0: 5% Sézary cells, but not meeting Sézary syndrome criteria; B2: Sézary syndrome. 2 E = Early (stages IA, IB, IIA) and L = later (stage IIB or greater). 3 Time from MF diagnosis to vitiligo diagnosis (months). 4 Location of vitiligo patches in relation to MF patches/plaques. * The patient had concomitant diagnoses of CTCL and vitiligo.
cation at the time of initial CTCL diagnosis and time at which patients developed vitiligo did not suggest that vitiligo was associated with MF progression or Sézary syndrome. Only one patient showed TNMB progression while 7 showed improvement and the remaining 17 had no change in classification. Vitiliginous macules and patches occurred in skin clinically ‘clear’ of MF patches and plaques in only 4 patients, whereas they occurred only in areas of MF involvement (11 patients) or areas of Dermatology 2015;230:143–149 DOI: 10.1159/000368772
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24 0* 12 24
Personal autoimmune disease
Age (per year) CTCL clone phenotype CD4+CD8– (reference) CD8+CD4– CTCL disease stage Early (IA, IB, IIA) (reference) Late (IIB, III, IVA, IVB) Methotrexate No (reference) Yes CD4 antibody No (reference) Yes Topical nitrogen mustard No (reference) Yes PUVA No (reference) Yes
Hazard ratio
p
0.973
0.0334
12.6
0.0001
2.3
0.0482
3.86
0.0178
5.43
0.0282
0.33
0.0220
0.31
0.0339
Color version available online
Table 2. Results of Cox proportional hazards modeling for development of vitiligo
a
b
Medications were adjusted for disease stage.
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Fig. 2. Vitiligo under Wood’s lamp illumination. Vitiligo involving the axilla clinically (a) fluoresces bright white under Wood’s lamp illumination (b). Hypopigmented MF lacks this fluorescent char-
acter (not shown).
Discussion
Vitiligo is characterized by the progressive destruction of melanocytes, resulting in depigmented macules and patches [5]. Although post-inflammatory hypopigmentation and hypopigmented MF can be confused with vitiligo clinically, the combination of patient demographics, appearance of all patients’ lesions under Wood’s lamp illumination and biopsy results supported diagnoses of vitiligo in our patients (fig. 2). Post-inflammatory hypopigmentation is characterized by hypopigmented patches that do not fluoresce brightly under Wood’s lamp illumination, and biopsy shows presence of melanocytes along with dermal melanophages [13]. Hypopigmented MF typically occurs in young, darker-skinned patients with histology revealing features of MF and preservation of melanocytes [14]. The clinical morphologies and distriHerrmann /Syklawer /Tarrillion /Duvic / Hughey
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both MF-involved and MF-uninvolved skin (8 patients). In all 7 cases where vitiligo was biopsied, no evidence of MF was identified in the depigmented skin specimen. Immunohistochemical analyses of MF lesions identified that malignant infiltrates were CD4+CD8– in most cases, but 3 patients had CD8+CD4– MF phenotypes. Finally, our cohort underwent diverse treatment regimens, including differing combinations of topical, systemic and/or lightbased therapies prior to their diagnoses of vitiligo. The results of Cox proportional hazards modeling of possible risk factors for developing vitiligo in the setting of CTCL are summarized in table 2. Younger age (HR: 0.97 [3% decreased risk per year]), late-stage disease (HR: 2.30), and CD8+CD4– MF phenotype (HR: 12.6) were factors associated with increased risk of vitiligo, although only 3 total patients had CD8+CD4– MF phenotypes. When medications were adjusted for disease stage (early versus late), methotrexate (HR: 3.8) and CD4 antibody (HR: 5.43) were associated with increased risk of developing vitiligo, while nitrogen mustard (HR: 0.33) and PUVA (HR: 0.31) showed decreased risk. The total number of patients treated with each of these modalities was low: 5 and 2 patients had been on methotrexate and CD4 antibody, respectively.
tumor cells directed against melanocyte antigens or from autoantibodies such as antityrosinase. In a more recent study that examined cutaneous lymphocytes in one patient with Sézary syndrome who developed vitiligo, vitiligo was found to be related to the presence of CD8+ T lymphocytes specific for melanocyte differentiation antigens melan-A/MART-1 and to a lesser extent tyrosinase and gp100 [11]. This may be similar to melanoma-associated depigmentation that develops in melanoma, which is thought to result from a CD8+ cytotoxic reaction against melanoma tumor cells [25]. Other studies have associated therapeutic agents, including treatment with PUVA and IFNα, with vitiligo in CTCL patients [9–11, 22, 26, 27]. Considering these reports collectively, it becomes evident that multiple factors have been implicated in the development of vitiligo in patients with CTCL. In our cohort of 25 patients, younger age, later disease stage and presence of CD8+CD4– malignant clones, although only three total patients carried this phenotype, were associated with the development of vitiligo. In patients with CD8+CD4– phenotypes, a malignant T cell clone with cytotoxic properties may have contributed to melanocyte destruction, as CD8+ malignant infiltrates have been identified in some patients with CTCL who developed vitiligo [28]. A derangement in CD4+ cells may have also generated an immune environment permissive for vitiligo. Multiple studies have suggested that in both early-stage CTCL [29] as well as in patients with later-stage disease undergoing treatment [30], a T-helper immune response dominates, and T-helper cytokines have also been identified in patients with vitiligo [31]. Although we did not investigate specific signaling molecules directly, it is possible that the pro-inflammatory cytokine IL-17 plays a role, as higher levels of IL-17 have been documented in both patients with MF [32, 33] and vitiligo [34]. IL-17 signaling promotes an inflammatory environment that could play a role in vitiligo by increasing levels of reactive oxygen species. Finally, it also may be that a CTCL-induced alteration of regulatory T cells (Tregs) is related to the development of vitiligo. Several studies have suggested that early MF lesions harbor benign Tregs that help suppress malignant expansion, while more advanced disease stages show a paucity of Tregs [35]. In other reports the malignant T cells in some patients with Sézary syndrome have been shown to display Treg phenotypes themselves [35]. Since Tregs are crucial for maintaining peripheral tolerance and preventing inappropriate excessive immune reactions, it is possible that CTCL-induced perturbations in
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bution of depigmented lesions in our cohort further supported diagnoses of vitiligo over more general leukoderma. All of our patients had chalk-white macules and patches with mostly discrete convex margins, and all developed classic patterns of lesion distribution, including generalized vitiligo vulgaris, acrofacial or generalized mixed vitiligo. Moreover, as is often associated with vitiligo, many patients suffered from progressive depigmentation, which occurred despite improvement or even clearance of MF patches and plaques. Finally, none of our cohort had diagnoses of vitiligo prior to their developing MF, excluding the possibility of simple koebnerization of MF lesions. Although the etiology of vitiligo remains obscure, several theories have explained depigmentation. The biochemical hypothesis argues that an accumulation of toxic metabolites from melanogenesis destroys melanocytes [15], while the neural hypothesis proposes melanocyte destruction by neurochemical toxic mediators [16]. The impaired redox status theory maintains that the breakdown of free radical defense and an excess of hydrogen peroxide contribute to melanocyte destruction [17], while the theory of melanocytorrhagy suggests that genetically defective melanocyte adhesion results in the disappearance of melanocytes [18]. The most widely accepted autoimmune theory implicates cellular and/or humoral immune mechanisms in melanocyte elimination [19, 20]. Although each of these hypotheses has corroborating evidence, none fully accounts for all cases of vitiligo. It is therefore possible that vitiligo represents a ‘syndrome’ rather than one disease, with numerous but not mutually exclusive pathways leading to melanocyte disappearance, where complex interactions of biochemical, environmental and immunological events operate on a permissive genetic background. It is possible that other cutaneous diseases which alter the skin’s biochemical and signaling milieu impact this pathogenic process. Indeed, the development of vitiligo has been reported in sites of previously active psoriasis and atopic dermatitis [21–24]. Although rare, vitiligo has also been documented in patients with CTCL. In 1987, Alcalay et al. [8] reported a case of biopsy-confirmed vitiligo in a gentleman with Sézary syndrome. They suggested that a dense dermal lymphocytic infiltrate composed mainly of helper T cells contributed to melanocyte destruction by stimulating a cell-mediated cytotoxic process. More than a decade later, Bouloc et al. [9] described four erythrodermic CTCL patients who developed vitiligo during disease flares. It was hypothesized that depigmentation resulted from the cytotoxic activity of reactive
Tregs, particularly those leading to their decrease, set the stage for or even perpetuate/accelerate autoimmunity. Indeed, recent reports have shown that some vitiligo patients have either drastically decreased numbers of Tregs in vitiliginous skin [36] or functionally defective Tregs in their peripheral blood [37]. In our cohort, treatment with either methotrexate or CD4 antibody was associated with increased risk of developing vitiligo; however, few patients were treated with these therapies, and it is uncertain whether these associations are generalizable. In theory, medication-induced inflammation and reactive oxygen species or altered epidermal signaling may have played a role in melanocyte destruction. Fewer patients treated with nitrogen mustard or PUVA developed vitiligo; however, again, the total numbers treated were small. Topical nitrogen mustard and PUVA therapy have both been used successfully to achieve repigmentation in vitiligo [38]. PUVA therapy induces lymphocyte apoptosis and stimulates melanogenesis, which may explain the decreased incidence of vitiligo in patients treated with this modality. Future studies might prospectively analyze the degree and distribution of vitiligo as it relates to medication types, their doses and their withdrawal. In summary, younger age, non-Caucasian white race, presence of CD8+CD4– malignant clones, later disease
stage and treatment with methotrexate or CD4 antibody were associated with the development of vitiligo in some patients of our limited cohort. No factor was common to all patients, and we believe that our patient diversity supports the growing knowledge of the complexity of the pathogenesis of vitiligo. Multiple factors likely contribute to melanocyte destruction in patients with CTCL who develop this disease. Variation may depend on the distinct CTCL malignant clone, treatment regimen and individual genetics. Vitiligo may be best considered a ‘complex trait’, involving multiple genes as well as non-genetic factors. As further research refines its etiology, we may better understand those aspects that are most relevant to its occurrence in patients with CTCL.
Acknowledgements We would like to thank Dr. Aleodor A. Andea and Dr. Zendee P. Elaba for their help with histopathological photographs, analysis and interpretation.
Disclosure Statement The authors declare no conflicts on interest. There were no funding sources.
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