Fiona M. Lewis Lichen sclerosus (LS) is probably the most common condition affecting the vulva and can affect children and adults. LS in children and adolescents is discussed in Chapter 49. The first clinical description of lichen sclerosus is credited to Henri Hallopeau in 1887 [1]. He published a clinical lecture on a case of ‘lichen plan atrophique’, in which he described a 45‐year‐old female who gave a 3‐year history of vulval pruritus. She also had plaques on the forearms and lower back composed of ‘white spots with a cicatricial appearance and punctiform depressions’. He noted that there was considerable lichenification of the vulval skin. However, 12 years earlier, Weir had described a patient with vulval and oral ‘ichthyosis’, which is a good clinical description of lichen sclerosus [2]. Hallopeau went on to report more cases, and at the time he believed these to be a form of atrophic lichen planus [3]. The histological features of lichen sclerosus were formally described by Darier in 1892 [4], but he had commented on Hallopeau’s original case five years earlier. Many reports followed, and much confusion ensued due to inadequate data and the wide variety of descriptive terms employed. Early synonyms for lichen sclerosus included kraurosis vulvae [5], cardboard‐like scleroderma or Kartenblattformige Sklerodermie [6], white spot disease or Weissflecken Dermatose [7], white spot scleroderma [8], lichen albus [9], lichen planus sclerosus et atrophicus [10], and dermatitis lichenoides chronica atrophicans [11]. The term ‘balanitis xerotica obliterans’ was used in the 1920s [12] and is still used to describe male genital LS. Many authors, particularly in the European literature, regarded lichen sclerosus et atrophicus as a form of atrophic lichen planus. The terms ‘kraurosis’ and ‘leukoplakia’ persisted and were usually used to describe hyperkeratotic vulval lesions regarded as pre‐malignant. By the 1940s, several authors believed that lichen sclerosus was a distinct disease entity, and further studies in the 1960s highlighted the importance of vulval lichen sclerosus. The name lichen sclerosus et atrophicus was widely used in both the dermatological and gynaecological literature, but arguments against the atrophic nature of the disease resulted in the term ‘lichen sclerosus’ being formally adopted by the International Society for the Vulvovaginal Disease (ISSVD) in 1976 [13]. The major events in the terminology of lichen sclerosus are shown in Table 23.1. Table 23.1 Historical summary of terminology in lichen sclerosus. There are two peak incidences in females: one in the pre‐pubertal age group, starting between the ages of 3 and 4 years generally, and the second in the peri‐ and post‐menopausal woman. The average age at onset of symptoms is 50 years in adult females. However, it can start in the reproductive years, with 41% reported in one study [17]. The incidence is not known, and the presentation to different specialties and difficulties with under‐ and over diagnosis add to the inaccuracy. Wallace estimated it at 0.1–0.3% in dermatology clinics [16], and in a study of nursing home residents, 3 of 96 had LS [18]. A Dutch study does show an increase in the incidence of LS from 7.4 to 14.6 per 100 000 women in the years between 1991 and 2011 [19]. Familial incidence is well recognized, and a family history was present in 12% of 1052 women in one study [20]. It may affect both sexes, for example, father and daughter, and has been noted in identical and non‐identical twins [21]. In adults, LS is more common in females than males, with estimates ranging from 10:1 to 3:1 [22]. HLA antigens are important in the regulation of humoral immunity. The DR and DQ antigens are linked with autoimmune conditions, and DQ7 is found in 50% of adult females with LS [23]. There was also a suggestion that A2 might exert a protective role in that it tended to be absent in patients who had extensive extragenital lesions, and that linkage of DR4 with DQ8 was commoner in those without marked structural change of the anogenital area. Further work shows that DR17 may be protective against LS [24]. The gene encoding for interleukin‐1 receptor antagonist was related to increased severity [25], but polymorphism in the TNF∝ gene was not linked [26]. Genomic sequencing in two families showed changes in CD177, CD200, ANKRD18A, and LATS2 genes [27]. The pathogenesis of LS is not fully understood, but there are immunogenetic mechanisms that do shed some insight, although without sufficient evidence to fully explain the process. In male genital LS, the theory of urine micro‐incontinence as the prime aetiological factor is postulated [28], but some have speculated that there may be different pathogenetic processes in male and female genital LS [29]. Alterations in the cytokine profile are reported in LS [30]. Upregulation of pro‐inflammatory microRNA‐155 (miRNA‐155) is expressed in active immune cells and promotes Th1 differentiation. If there is reduced functioning of the Treg cells, autoimmune reactions can be induced. The increased expression of miRNA‐155 in LS may act by reducing the normal Treg function [31]. It has also been shown that there is a reduction in FOXO3 and CDKN1B tumour suppressor genes (related to increased miRNA‐155) [32]. The FOXO3 gene is involved in regulating fibroblast proliferation, and so if activity of this gene is reduced, increased fibroblast activity will follow. Extracellular matrix protein 1 (ECM1) is an important basement membrane protein [33]. Autoantibodies have been demonstrated [34], and these target the same area where matrix metalloproteinase 9 binds. This may lead to increased MMP9 collagenase activity and hence disruption of the basement membrane. Circulating antibodies were found in about 75% of patients with LS [35]. They were more likely to be found in those with a longer duration of disease, and so may be more involved in progression rather than initiation. Autoantibodies to bullous pemphigoid antigens BP180 and 230 have been demonstrated at the basement membrane zone [36,37] but circulating antibodies are not different from levels in controls [38]. An increase in CD1a+ Langerhans cells is seen at all stages of the disease, supporting the role of the skin immune system [39], and the lack of correlation between duration of symptoms and histological appearances suggests a continuing inflammatory process in which activated Langerhans cells may be involved [40]. Increased collagen synthesis was found in a small study [41]. This may be related to the focal increased thickening of the basement membrane that may be seen histologically. Reduced elastic fibres and an increase in collagen types I, III, and V have also been shown [42]. Fibrogenic cytokines may also stimulate collagen synthesis. IL4 is increased in early disease which is fibrogenic, and TGFß may continue synthesis in later disease [43]. Mechanisms of oxidative stress have been shown in LS [44]. Protein oxidation can be increased in the dermis, resulting in sclerosis and inflammation. Reactive oxygen species may expose new epitopes for an autoimmune process, and oxidative stress can enhance the accumulation of p53, a tumour suppressor gene that regulates the cell cycle [45]. Wild‐type p53 is increased in LS but no mutations are found [46], whereas this may occur in malignancy [47]. It has been shown that vulval skin affected by lichen sclerosus has a wide range of proliferative capacity and that high levels are associated with overexpression of wild‐type p53 [48]. P53 expression and epidermal cell proliferation is altered in vulval lichen sclerosus, compared with normal vulval skin and with extragenital lichen sclerosus [49]. Epigenetics occurs when there are functional changes in the genome that can lead to alterations in gene expression or phenotype. This phenomenon is shown in LS, where there is altered expression of isocitrate dehydrogenase enzymes and abnormal hydroxymethylation [50]. LS is known to exhibit the Koebner phenomenon where a dermatosis arises at sites of trauma. It has been described in scars of various types, including burns [51], surgical [52] and herpes zoster scars [53], and after laser hair removal [54]. It has also been reported at a vaccination site [55] in skin previously treated with radiotherapy [56,57], on a congenital haemangioma [58], and after sun exposure [59] and sunburn [60]. The finding of histological features identical to those of lichen sclerosus in some large skin tags has suggested that occlusion and pressure may be factors in the development of lichen sclerosus [61]. All the previous examples are of LS koebnerising at extra‐genital sites, but it has also been reported in the vulva after radiotherapy for a vulval squamous cell carcinoma (SCC) [62]. LS may develop in skin grafts and myocutaneous grafts [63]. It was noted that LS developed in a split‐skin graft transferred to the vulva from the thigh, whereas vulval LS skin reverted to normal when transferred to the thigh [64]. This has important implications for any grafting required after extensive vulval surgery in those with LS. There are inconclusive and conflicting results regarding infective agents in the pathogenesis of LS. Some variable acid‐fast bacilli were found in LS and morphoea [65]. The focus then moved to the spirochaete Borrelia burgdorferi [66]. The organism has been demonstrated using focus floating microscopy in 63%, but on polymerase chain reaction (PCR) testing, this was not confirmed in any case [67]. However, a study using vulval tissue showed no spirochaetal forms, and coccoid bodies that were seen appeared to be mast cells rather than bacilli [68]. Other studies have shown no link [69]. Epstein‐Barr virus was found in 26% of cases, but the significance is unclear [70]. In common with other studies, this showed no association between human papillomavirus (HPV) and LS. As LS tends to occur at two stages in life when there is a low oestrogen state, hormones have been studied but there is no evidence that they play any causative role, and indeed, hormonal treatment does not have any therapeutic effect on the disease. Lower levels of dihydrotestosterone were found in patients with LS, and it was suggested that a reduction in the enzyme 5∝‐reductase might be involved [71]. There was a loss of androgen receptors reported [72], but others have suggested that this may be a secondary rather than primary issues [73]. In another study, all patients with LS were taking an oral contraceptive pill as compared with 66% of controls, and it was suggested that the anti‐androgenic properties may trigger LS in those who were genetically susceptible [74]. LS has been linked to some drugs. There was an increased use of non‐steroidal anti‐inflammatory drugs in one series with less likelihood of patients taking ACE inhibitors or beta blockers [75]. The development of LS has been associated with imatinib [76] and nivolumab [77]. Galectin 7 is a keratinocyte protein which inhibits dermal fibroblasts and increases collagen I and III. This is overexpressed in LS [78]. The histology of classic LS is usually straightforward, but histological features can vary with the stage of disease [79], although they do not correlate with length of symptoms [40]. In early or atypical disease, the classical features may not be seen, and this is where clinicopathological correlation is vital. Some would suggest that biopsy is not relevant if clinically typical [80], but this can depend on site of biopsy, experience of the clinician and pathologist, and the effect of previous treatment. For diagnosis, biopsy should be done in treatment‐naïve patients, as an ultrapotent topical steroid can reverse clinical and histological change, making diagnosis impossible. In established disease, the epidermis is thin and flat with a subepidermal hyalinized band, dermal oedema, and a lymphocytic infiltrate of mainly CD8+ cells under this (Figure 23.1). The elastin fibres are reduced in the area of sclerosis, and extravasated red cells are commonly seen. Immunofluorescent studies may show fibrin deposition at the epidermal junction [81]. There are some who have hyperkeratosis clinically, and this can be confirmed histologically with acanthosis and elongated rete pegs (Figure 23.2). This is important to note as this may be the group at an increased risk of malignant change. Superimposed lichen simplex can be seen as a result of chronic itching and scratching before treatment. Eosinophils are not uncommon in LS [82] without any associated autoimmune disease or drug reaction. The diagnosis of early LS may be more challenging. The sclerotic band is not always seen [83], and it may present as an interface dermatitis with a lichenoid lymphocytic infiltrate, lymphocyte exocytosis, basement membrane thickening [84], and irregular epidermal hyperplasia. There may be early hyalinisation below the basement membrane and around blood vessels which is highlighted by Periodic acid–Schiff (PAS) staining. As the disease progresses, the inflammatory band is pushed down and may not be seen in late lesions. Psoriasiform hyperplasia may be seen [85]. Figure 23.1 Lichen sclerosus: typical histological features. Thinning of epidermis, hyalinised band of collagen, and lymphocytic infiltrate. Figure 23.2 Lichen sclerosus, hypertrophic type with hyperkeratosis and elongated rete ridges. Electron microscopic features shows abnormalities of the collagen fibres which are packed together with some round structures. It is suggested that immune complex deposition and alteration in matrix proteins may give the appearance of hyalinization seen on light microscopy [86]. The main histological differential diagnosis is that of lichen planus [87], and this may be difficult in the early stages if there is a lichenoid infiltrate. However, in LP there is no basement membrane or epidermal thickening.
23
Lichen Sclerosus
Historical aspects
1875
Report of possible vulval and/or oral lichen sclerosus as ‘ichthyosis’ [2]
1885
Kraurosis vulvae described [5]
1887
Lichen plan atrophique and extra‐genital lichen sclerosus described [1]
1892
Histopathology of lichen sclerosus described and term lichen plan sclereux used [4]
1920
Vulvectomy used as treatment for kraurosis vulvae [14]
1966
Arguments against vulvectomy in management [15]
1971
Clinical features of lichen sclerosus defined and association with auto‐immune disease noted [16]
1976
Lichen sclerosus accepted as terminology by ISSVD, and terms ‘lichen sclerosus et atrophicus’, ‘leukoplakia’, ‘neurodermatitis’, ‘leukokeratosis’, ‘Bowen’s disease’, ‘erythroplasia of Queyrat’, ‘carcinoma simplex’, ‘leukoplakic vulvitis’, ‘hypoplastic vulvitis’, and ‘kraurosis vulvae’ should be abolished [13].
1989
Lichen sclerosus established as separate condition in ISSVD classification of non‐neoplastic epithelial disorders
Epidemiology
Genetics
Family history
HLA antigens
Genome sequencing
Pathophysiology
Cytokines, T‐cell regulation, and microRNA 155
Autoantibodies
Collagen
Oxidative stress
Cell proliferation
Epigenetics
Trauma
Infection
Hormones
Others
Histological features
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