Acral Vitiligo and Lichen Sclerosus - Association or a Distinct Pattern?: A Clinical and Histopathological Review of 15 Cases

Abstract

Background:

Acral or acrofacial vitiligo (AFV) with bilateral lesions over the extremities and face is considered as a transitional form that may progress to generalized vitiligo. Oral and genital mucosal lesions are often integral to this pattern. Lichen sclerosus (LS) in a milder expression, results in oral and genital vitiligoid depigmentation without textural changes and thus needs to be differentiated from AFV.

Materials and Methods:

We reviewed 217 cases of AFV recorded over a period of 12 years.

Results:

One hundred and sixteen cases had associated oral/genital lesions. Among these, 15 patients demonstrated typical clinical as well as histological features of LS.

Discussion:

Coexistence of typical LS essentially among oral and genital lesions of acral vitiligo suggests that acral vitiligo might be a distinct sub-group of NSV. Since both the diseases have an autoimmune basis, the co-existence may be explained by epitope spreading, as a result of interface dermatitis seen in vitiligo. In addition, the possibility of a common genetic predisposition needs to be explored.

What was known?

• Acral or acrofacial vitiligo is a common form of vitiligo perceived to be transitional in the evolution of generalized vitiligo. Oral and genital lesions are frequently associated.

• Unlike the facial lesions, the acral lesions are resistant to treatment.

Background

Vitiligo continues to be an enigmatic disease defying a consensus on the definition and classification. Acrofacial vitiligo (AFV) is currently classified as a form of generalized vitiligo (GV), under non-segmental vitiligo (NSV).[1,2] However, there is no scientific evidence of these being distinct diseases as they may evolve in time in to generalized vitiligo.[1] AFV can be seen with either a limited involvement of the lips, tips of the fingers/toes and penile shaft as the ‘lip-tip’ form;[3] or, acral vitiligo (AV)[4] in various stages of centripetal progression to the trunk. Confusion prevails over the status of oral and genital vitiligo, because mucosal vitiligo has been identified as a separate form.[5] Mchepange et al. have reported mucosal vitiligo in association with AFV in a significantly large number of cases and suggested that it should be considered within the spectrum of AFV.[6] We concur with this opinion for one more compelling reason that oral and genital mucosal lesions often involve the surrounding non-mucosal skin as well [Figure 1]. Medical and dermatological glossaries define ‘Acral’ as a relative term indicating an extremity or peripheral area. Although limb lesions are primarily considered as acral, the term does not exclude involvement of ears, nose, lips and genital areas (Ex: acral cyanosis). Since AFV has limited connotation, we believe it would be simpler to use the term ‘acral vitiligo’ (AV) to include all peripheral lesions. This name is also appropriate so as to differentiate it from classic GV that evolves rapidly with central body preponderance of lesions from the beginning[4] [Figure 2].

Figure 1.

Acral vitiligo lesions persisting over 30 years in a 60-year-old male. Oral (a) and genital involvement (b) also seen

Figure 2.

Fulminate generalized vitiligo with dominant trunk involvement

AV is the most common presentation among our patients. Over the years we have observed a co-occurrence of LS in a number of cases. Moreover, vitiligoid lichen sclerosus (VLS), a milder and superficial subtype of LS,[7,8,9] is also reported among patients with oral and genital depigmentation, thus sharing features with AV and LS.[10] Therefore, we set out to explore the clinical and histological features of AV cases involving the oral and genital areas and investigated the association of LS.

Materials and Methods

We retrospectively reviewed the clinical and histological features of vitiligo and vitiligoid lesions (asymptomatic idiopathic macular depigmentation which does not fit in with the known clinical patterns of vitiligo and cannot be attributed to post inflammatory depigmentation of commonly known interface dermatitides), that presented to our private dermatology institute, frpm 2002-2013. Clinical lesions have been routinely photographed (with consent from patients), biopsies taken and histological features recorded in all cases. Diagnosis of LS was made on obvious clinical atrophy/sclerosis confirmed by histological features, i.e. diffuse vacuolar interface dermatitis of varying grades associated with dermal sclerosis in hematoxylin and eosin (H and E) stained sections.[11,12] Cases with clinical suspicion of LS but contentious presclerotic histological features with vacuolar interface dermatitis alone were excluded.

Results

Vitiligo lesions were classified as focal in 73, focal segmental in 151, multifocal with no bilateral symmetry in 60, generalized bilateral symmetrical lesions with trunk involvement in 110 and AV with preponderant bilateral symmetrical acral involvement in 217 cases. The AV group of 217 was further subdivided as: Those with lesions essentially limited to the tips of fingers and toes (47), lesions extending up to the wrists and ankles (75), lesions extending up to the elbows and knees (71) and lastly, 24 cases with lesions beyond the elbows and knees associated with a few isolated trunk lesions considered as AV progressing to GV. Among these four AV sub-groups, 116 patients (females 61 and males 55) had associated lip/genital skin involvement, of which 15 (females 3 and males 12) had clinical features suspected of LS in one or more areas of lip, genital and acral involvement. Since biopsies were taken from more than one area in a few cases, histological features consistent with LS were observed in 21 lesions. A flow chart diagram [Figure 3] and Table 1 summarize these observations.

Figure 3.

Flow chart showing 15 cases of LS associated within the acral vitiligo spectrum

Table 1.

Profiles of AV cases with concurrent features of LS

The age of patients in this group of 15 varied from 10 to 60 years and duration of disease from 3 months to several decades. Only three were females of which two had LS of lips [Figure 4] and one had guttate LS among acral lesions of vitiligo [Figure 5]. Among 12 males, 9 had phimosis associated with depigmentation [Figure 6] and circumcision was performed. The remaining three had mild textural changes without phimosis [Figure 7]. Nonetheless, all the 12 had histological features of LS. All the LS lesions among males as well as females were asymptomatic, noted on routine examination. In addition to the typically larger macular AV lesions, punctate and guttate lesions were often observed and in two instances, these were palpably thick with histological features of LS on biopsy [Figures 5 and 8]. One male patient who had AV for many years, developed features of LS in all the three areas (acral, oral and genital); and, further on developed squamous cell carcinoma (SCC) over the lower lip [Figure 8].

Figure 4.

AV (a, b and d) with lips showing thick milky white depigmentation and typical histopathological features (c) of progressive LS. Hematoxylin and eosin (H and E, ×20)

Figure 5.

AV (a-c) with a guttate lesion over the hand showing hyperkeratosis, thin epidermis and extensive dermal sclerosis as in resolved LS (d). H and E, (×20)

Figure 6.

AV with phimosis (a) and depigmentation (b and c) biopsy of prepucial skin (d) showed typical features of LS. (H and E, ×10)

Figure 7.

(a and b) AV of both hands associated with atrophic depigmentation of prepuce. (c) Focal lichenoid infiltrates typical of vitiligo in marginal biopsy from the wrist (H and E, ×20). (d) Prepucial biopsy showing thin epidermis and dermal sclerosis typical of late stage LS. (H and E, ×10)

Figure 8.

A (a) AV persisting over 3 decades in a 47 year old male with oral, genital involvement and guttate acral lesions in 2001. (b). Same patient as in 8a seen after 8 years- The lower lip showing leucoplakia and a crusted erosion, which on biopsy had features of invasive SCC. (c) Sclerotic guttate lesion over dorsum of hand.(d) Prepucial vitiligo lesions transformed in to milky white depressed atrophic plaques

Oral and genital involvement was also seen in 29 of 110 patients with GV, in contrast to AV where 116 out of 217 patients had oro-genital inviolvement (P < 0.05) None of the oro-genital lesions in the GV group had clinical features to suspect LS and biopsies taken from genital lesions in a random sample of 6 males had also not demonstrated histological features of VLS.

Discussion

Vitiligoid LS (VLS) as a superficial form of LS, possibly unique to dark skinned races was first proposed in 1961 by Borda et al., from Argentina. We have also reported this subtype of LS among our patients presenting with oral and genital depigmentation.[7,10] Borda et al. further proposed that ‘lesions of vitiligo may have histologic changes suggestive of LS, and lesions typical of vitiligo, both clinically and histologically, are found in conjunction with LS’.[13] Although the clinical context in which those observations were made was not mentioned, our series not only confirmed such concurrent features of LS and vitiligo but, further demonstrated that they occurred among AV cases that had oral and genital lesions. In contrast, oral and genital involvement was not as frequent in GV (29 of 110) as in AV (116 of 217) and association of LS was not observed in GV. Prospective long-term studies comparing the two sub groups of vitiligo are indicated to substantiate and explain this anomalous observation. We had sub-grouped AV depending on the extent of acral involvement [Figure 1], but were unable to find any association/predictive value between the extent of acral vitiligo (as identified by the sub-grouping) and oro-genital involvement. However, an impression of centripetal progression in AV was derived from this retrospective cross-sectional study. Long-term prospective studies are necessary to confirm this finding.

Although association of LS with GV has not been reported in large epidemiological studies,[14] there have been few reports of vitiligo in association with stereotypical LS. In all such reports, the diagnosis of vitiligo was based on clinical impression, which therefore becomes contentious, since macular depigmentation can be a presentation of LS, i.e. VLS.[7,8,9,10] Further, there was no mention made regarding the type of vitiligo, i.e. SV or NSV/AV.[15,16,17,18] It is interesting that genital LS has been reported within an area of segmental vitiligo over the thigh extending into the genital area.[19] It would be helpful if future reports specify vitiligo sub-types when reporting association of LS, to see if our observations regarding association of LS and AV can be replicated. Racial predilection and clinicians overlooking the atypical oral and genital lesions in the absence of symptoms could be the reasons as to why this mixed pattern of vitiligo and LS eluded notice so far.

Co-existence of two diseases that result in depigmentation and occur within a localized area may question the diagnosis, as the lesions could be within the larger spectrum of a single disease. Although vitiligo and LS are both considered as autoimmune diseases, the target antigen in LS is unknown and in the absence of more definitive diagnostic tests, coexistence of these two diseases among our patients is favoured, on clinical and histological grounds. It is possible that epitope spreading as a result of the lichenoid inflammation in vitiligo, may result in LS. The histories suggest that LS changes appeared subsequent to AV and are unrelated to the age of the patient or duration of the disease. However, they are essentially associated with lip and genital involvement in AV, which are also the usual areas affected by LS. Among those cases of AV with lip/genital involvement, the observation that only few patients (15 of 116) developed LS changes may suggest a genetic predisposition to both diseases. However, the genetic basis of vitiligo is described to be ‘complex’, involving multiple genes[20] and no clear genetic transmission patterns are identified. Increased incidence of LS among close relatives is well known.[21] Although there are no apparent common genetic factors, this may indeed be a true association considering the concurrent presence of vitiligo and LS in a small but significant number of AV cases. Despite females (61) with oral/genital lesions outnumbering males (55), it is difficult to speculate why this association of genital LS (12 males) was not seen in female patients. A recent hypothesis that occlusion effect of urine might predispose uncircumcised men to the development of LS[22] might co-existence of genital LS selectively in men with AV. However, this does not explain the oral involvement seen in both sexes and this theory, is yet to be validated. It is more relevant that one of our male patients had LS changes in all three areas and the longstanding lip lesion developed SCC. Predisposition to SCC is well documented with genital LS,[23] but vitiligo despite the absence of pigment protection is not known for such predisposition.[24] However, in this patient, LS had interposed between lip vitiligo and SCC. PUVA or natural UV exposure could have been the additional aggravating factors.

A common pathogenetic mechanism shared by vitiligo and LS is interface dermatitis resulting in depigmentation: primary to destruction of melanocytes in the former and as an adjuvant phenomenon in the latter. It is also observed that longstanding lesions of vitiligo may result in mild clinical atrophy or sclerosis.[4,25] However, such features do not pose problems of differentiation from LS, in which the interface dermatitis is diffusely vacuolar with the basement membrane alterations persisting after the lymphocytic infiltrate recedes down into mid-dermis. This feature in turn results in a hyalinized papillary dermis which is totally unlike the mild fibrous sclerosis seen in longstanding vitiligo lesions or other interface dermatitides like atrophic lichen planus and discoid lupus erythematosus.

Many inflammatory diseases in dermatology with unknown etiopathogenesis are defined by a set of clinical and histopathological criteria. Vitiligo suffers from the drawback that diagnosis is entirely made on clinical observation of acquired idiopathic macular depigmentation. Therefore, many clinical patterns have been described, of which, GV with bilateral symmetrical involvement and SV, are considered distinct. Our observations suggest that the status of AV in the larger spectrum of vitiligo is also distinct because of persistence over years; intermittent centripetal progression to trunk, poor response to usual treatment modalities[26] and a predisposition to develop LS in few cases.

What is new?

• Acral vitiligo with centripetal progression to the trunk is distinct from generalized vitiligo that develops with preponderant early involvement of trunk.

• Coexistence of typical lichen sclerosus essentially among oral and genital lesions of acral vitiligo suggests that it might be a distinct sub-group of NSV.