Clinical and histopathological spectrum of genital lichen sclerosus in 133 cases: Focus on the diagnosis of pre-sclerotic disease

Clinical spectrum

Associated lip involvement was seen in 14 patients and extragenital lesions in ten patients. There was no association with morphea. Among males, exclusive scrotal skin lesions in 15 cases [Figures 4a-d], perianal areas in four and crural areas in five cases were seen. Among females, the introitus, clitoris and periurethral areas were primarily involved with atrophic depigmentation, sometimes accompanied by erythema. The lesions extended to the perianal, groin and pubic areas in three patients [Figure 3c].

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Figure 4(a-d):

Different presentations of scrotal lesions

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There were four cases (two male, two female) presenting with early squamous cell carcinoma arising within the lesional skin in genital lichen sclerosus that had persisted for over three decades.

Histological spectrum

Lichen sclerosus is known to demonstrate three histological stages⁶ as (1) early or pre-sclerotic stage with interface dermatitis, lichenoid or vacuolar type, (2) progressive upper dermal sclerosis underpinned by a band of inflammatory cellular infiltrate and (3) late resolved stage with scant cellular infiltrates with loss of adnexal, vascular structures and homogenisation of the dermis. Of these three, only the progressive stage is considered as the diagnostic stereotype and the other evolutionary stages have not been characterised. With the advantage of examining large number of cases in different clinical stages and histological sections of biopsies taken with multiple sections from the circumcised prepucial skin, we were able to identify sequential and transitional patterns of evolution and resolution [Table 1]. The most initial event appears to be lymphocytic infiltration at the papillary interface [Figure 5a] destroying the basement membrane and capillaries resulting in homogenised and widened papillae [Figure 5b]. Subsequently, the thickened basement membrane formed thick bands around the rete ridges [Figure 5c] and newly formed capillaries merged with the surrounding hyalinised dermal matrix. The inflammatory band appears to shift away from the flatter epidermis leaving an oedematous layer in its wake, with destruction of vascular and adnexal structures, which later gets replaced by homogeneous matrix substance. At the same time, abnormally dilated vessels with thick walls in horizontal orientation were prominently seen within and below the inflammatory band [Figure 6]. Resolved lesions had a consistent histological picture of atrophy with thin epidermal layer and a loose dermal matrix with striking absence of adnexal and vascular structures. [Figure 2], Biopsy from different areas of the same lesion may show varying features, depending on the stage of evolution of the disease.²⁹ In a few cases, there was epidermal hyperplasia (instead of flattening) with basilar infiltration of lymphocytes accompanied by massive dermal sclerosis. However, a prognostic value cannot be inferred for such features as the numbers are small and as a cross sectional study, it was not possible to determine the time periods of each stage and assess the natural course of disease. The overall impression is that the disease resolves after an indefinite period spontaneously over years. Treatment definitely helps to hasten the resolution and alleviate the symptoms. Multiple sections from the circumcised prepuce consistently demonstrated more advanced stages on the mucosal side indicating that this was involved before the outer surface.

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Figure 5a:

Papillary lymphocytic infiltrate destroying the basement membrane (haematoxylin and eosin ×400)

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Figure 5b:

Widening of papillae, thickened epidermal and capillary basement membrane merging with papillary sclerosis. New capillary formation is also appreciated. Black arrow shows basement membrane thickening is even evident around the capillaries (haematoxylin and eosin ×200)

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Figure 5c:

Thickened basement membrane forming thick bands around the rete ridges (haematoxylin and eosin ×200)

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Figure 6:

Abnormally large blood vessels with thick walls within the dermal inflammatory band (haematoxylin and eosin ×100)

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Discussion

Familial aggregation was an interesting observation but as the numbers were small in our study, no clear hereditary pattern was identified. Association of lichen sclerosus with systemic autoimmune diseases appears to be ambiguous.^11-13 We did not find any such association in this study.

The true incidence and prevalence of lichen sclerosus among genital lesions is probably understated as pre-sclerotic and vitiligoid lesions cannot be identified without a biopsy. Vitiligoid lichen sclerosus is a superficial subtype of lichen sclerosus. All the three histological staging patterns were seen on histological examination of these lesions. This subtype was seen in 14% of our patients. We observed vitiligoid depigmentation at the peripheral spreading margins of some typical lichen sclerosus lesions, indicating that vitiligoid changes occurred early in the development of lichen sclerosus. Vitiligo and lichen sclerosus are both interface dermatoses; the inflammation not progressing beyond destruction of melanocytes, in the former. In few instances, the inflammation in vitiligoid lichen sclerosus may also subside early before the emergence of dermal sclerosis, thereby resulting only in post-inflammatory depigmentation. In such cases, distinction from vitiligo becomes difficult both on clinical and histological grounds.

Diagnosis of early lichen sclerosus

Genital lesions associated with obvious clinical atrophy/ thickening or erosions pose no clinical diagnostic problems and a biopsy in such cases invariably shows fairly advanced disease with progressive sclerosis and irreversible structural damage. In our series, the pathognomonic histological picture of lichen sclerosus [Figure 1] was seen in about 50% of cases [Table 1]. Thus, if strict criteria for the diagnosis of lichen sclerosus had been applied, approximately half the cases would have escaped early diagnosis.

The clinical and histological diagnosis of the early disease is especially problematic when the genital, groin and perineal areas are exclusively affected as non-specific inflammatory lesions and clinically they can easily be confused with atypical psoriasis, seborrhoeic dermatitis, nutritional deficiency syndromes, non-specific intertrigo or scrotal dermatitis. However, histopathological differentiation between lichen planus with saw toothed rete pegs and an evenly elongated pattern in psoriasis is not difficult.

Occasionally, an overlap of lichen sclerosus and lichen planus has been considered^30-32 in cases of early lichen sclerosus where a dense lichenoid infiltrate and an invisible basement membrane makes it difficult to exclude genital lichen planus. At a later stage however, when the cellular infiltrate abates at the interface, the emergence of basement membrane thickening [Figure 5b] becomes a clue to the diagnosis of early lichen sclerosus.³³ We therefore suggest that the combination of basilar infiltration of lymphocytes along with vacuolated and/or thickened basement membrane should be considered diagnostic of pre-sclerotic lichen sclerosus [Figure 5c].

Pathogenesis

Unlike other interface dermatitides, the band of inflammation in lichen sclerosus slowly recedes from the epidermal interface along with the deposition of hyaluronic acid in the papillary dermis.^34,35 Altered distribution of tenascin, fibrinogen and fibronectin has been reported indicating a significant disorganisation of the extracellular matrix.³⁶

Vascular changes in lichen sclerosus are an under-recognised feature.^37-39 The presence of a band-like inflammation, despite the hyaline band of sclerosis separating the inflammatory cells from the epidermal basement membrane, suggests that inflammation possibly follows the capillary basement membranes (angiogenesis) in the dermis. We noted destruction of papillary capillaries in early lesions [Figure 5a-c], gross thickening of basement membrane around capillaries with enormously dilated dermal vessels in the progressive stages [Figure 6] and complete absence of normal vascular channels in resolved lesions [Figure 2]. This indicates that inflammation with destruction of papillary capillaries involves the dermal vasculature progressing downward along the vertical channels to the superficial horizontal plexus. The thin basement membrane of capillaries is usually not visible in histopathological sections but becomes visibly thickened when it becomes the specific target of inflammation.

The presence of CD4 and CD8 lymphocytes in the inflammatory infiltrate and increased expression of HLA DR suggests a T cell-mediated reaction.^10,40 Humoral mechanisms may also be involved and autoantibodies against extracellular matrix protein have been observed in 75% of patients with lichen sclerosus.^8,9,41 While the significance of humoral^8,9 and cellular immune mechanisms in the actual pathogenesis is not clear, the involvement of the basement membrane as the likely target is evident from the histopathological spectrum. The specific antigen targeted among the components of basement membrane remains elusive,¹⁰ but ultra-structural studies have reported several small holes in the basement membrane as well as its complete absence in some places.³⁹

The specific role of ECM 1 protein in the reconstruction of basement membrane is unclear. A parallel has been drawn with lipoid proteinosis, a hereditary disease in which pathogenic mutations in ECM 1 gene generate similar abnormalities in dermal blood vessels and a hyaline appearance of dermis as seen in established lesions of lichen sclerosus.³⁷ It is, however, considered angiogenic⁴¹ and may indirectly contribute to the pathogenesis by enhancing the target, i.e., the basement membrane around new blood vessels. Thickening of basement membrane appears to be a natural response of the homeostatic repair mechanisms at the interface. A sequence of events causing destruction and regeneration can explain the enormously thickened basement membrane seen in some cases. Enormously large and dilated vessels with thick walls within the inflammatory layer may be a compensating phenomenon for the loss of vascular network in upper layers.

Limitation

We studied only haematoxylin and eosin stained sections.The presence of basement membrane thickening could have been better illustrated with periodic acid–Schiff staining.