Inflammatory Dermatoses Affecting the Dermis or Both the Epidermis and Dermis of the Vulva



Fig. 5.1
Lichen planus. Introital erythema with small foci of ulceration showing well-demarcated borders (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)



A313723_1_En_5_Fig2_HTML.jpg


Fig. 5.2
Lichen planus. Whitish hyperkeratotic lesions with conspicuous Wickham striae (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)


Vulvar LP can adopt three distinctive clinical forms: the most common is erosive LP, accounting from 74 % [6] to 95 % [7] of cases, followed by papulosquamous LP that usually appears in the setting of generalized disease, whereas the hypertrophic variant of LP is quite rare [1]. Erosive lichen planus is characterized by mucosal fragility with quite well-demarcated areas of erosion and ulceration (Fig. 5.1). In up to 70 % of these patients, the vaginal mucosa is also involved [1, 8]. Hemorrhage and scarring can lead to synechiae, introital stenosis, or vaginal obliteration. Papulosquamous LP appears clinically as pruritic keratotic papules on a slightly hyperkeratotic background. These papules are usually pinkish and poorly circumscribed rather than being small, well delimited, and violaceous as in cutaneous surfaces [8]. In hypertrophic LP the lesions are thick hyperkeratotic plaques that may resemble a vulvar squamous cell carcinoma (SCC) [8].

The incidence of LP in women is approximately 1 %. The most common location is the oral mucosa [9]. Twenty-five percent to 65 % of women with oral disease also present with vulvar and vaginal LP, which is often asymptomatic [1012], constituting a triad known as vulvovaginal-gingival syndrome or plurimucosal LP [8, 13]. Vulvovaginal involvement is also common in women with cutaneous LP [14] and LP cicatricial alopecia [15]. In a study from the United Kingdom, 19.2 % of patients with vulvar LP also presented with LP alopecia [15]. Frontal fibrosing alopecia, a variant of lichen planopilaris, was the most common variant and it was found in a proportion similar to that of the general population [16]. Interestingly, all patients with vulvar LP and frontal fibrosing alopecia also presented with oral involvement [15]. Visceral mucosal surfaces can also be affected by LP; 42 % of individuals with esophageal LP also presented with vulvar disease in one study [17], and there is one report of LP in the uterine cervix [18].

Autoimmune diseases are frequently present in patients with vulvar LP; this association was found in 29 % of patients of a series [19], the most common comorbidity being autoimmune thyroiditis (15 %), followed by vitiligo (5.5 %), alopecia areata (3.9 %), and celiac disease (2.4 %), whereas chronic active hepatitis accounted for less than 1 % of cases.

Some women present with hybrid forms of LP and lichen sclerosus, and superposition of the two entities may be observed. It has been suggested that LP may act as a triggering factor in the development of LS [20].



Etiology and/or Pathogenesis


Although the exact pathogenesis of vulvar LP is not known, genetic and autoimmune factors are clearly implicated. Familial cases of LP are rather common, often in association with HLA class II antigens; specifically, the HLADQBI 0201 allele is associated with some cases of vulvovaginal-gingival syndrome [21]. The association of LP with other autoimmune diseases and the presence of circulating autoantibodies in a frequency higher than controls are arguments in favor of an autoimmune etiology [19, 22]. Furthermore, the lymphocytic infiltrate in LP exhibits an autoimmune phenotype, corresponding to a Th1 interferon (IFN) gamma-induced immune response [23] with activated T cells targeting basal keratinocytes. Indirect immunofluorescence using sera from 56 individuals with a definitive clinical diagnosis of erosive genital LP showed epidermal-binding and basement membrane zone antibodies, which were also present in the sera of 61 % of these patients [24]. Recent evidences also support an association between beta-blockers and nonsteroidal anti-inflammatory treatments and the presence of vulvar LP [25].


Prognosis or Course


Vulvar LP is a long-lasting inflammatory condition with great variation in severity of symptoms and response to treatment. The course is in general more prolonged than in the nongenital cutaneous counterpart, but the risk of malignant transformation is moderately low. Combining the results of four case series published in the literature, Simpson et al. [26] found infiltrating vulvar SCC in 1.3 % of patients. A multicenter case study yielded a similarly low percentage of 2.3 % [27]. At any rate, cases of aggressive malignant transformation exist [28], thus making periodical control of these patients and histopathological examination of suspicious lesions advisable.


Histopathology


The histologic appearance of LP in the vulva is similar to that in other locations although, often, changes displayed in mucosal LP are subtler than in its cutaneous counterpart. Thus, the findings can be quite equivocal for those who do not routinely review this type of pathology under the microscope. The most consistent finding in all cases of vulvar LP is a lymphocytic infiltrate forming a band in the superficial connective tissue that obscures the basal epithelial layer (Fig. 5.3), but the intensity varies greatly from case to case and can be limited to a small number of cells sprinkling the mucosal basal layers (Fig. 5.4). Plasma cells can also be abundant, as in any mucosal inflammation. The epidermis may be either atrophic or hypertrophic with the distinctive sawtooth silhouette of rete ridges (Fig. 5.5), although it is not always present, and can be observed only focally. It is common to find hypergranulosis, some degree of hyperkeratosis with occasional areas of parakeratosis (Fig. 5.3). An intense thickening of the horny layer is the hallmark of the hyperkeratotic variant of vulvar LP or the presence of lichen simplex chronicus changes due to rubbing (Fig. 5.6).

A313723_1_En_5_Fig3_HTML.jpg


Fig. 5.3
Lichen planus. Epithelial hyperplasia with dense lymphocytic infiltrate at the basal layer and compact hyperkeratosis with small foci of parakeratosis


A313723_1_En_5_Fig4_HTML.jpg


Fig. 5.4
Lichen planus. The biopsy shows scant lymphocytic infiltrate at the basal layer. Nevertheless, the presence of hypergranulosis supports the diagnosis of lichen planus


A313723_1_En_5_Fig5_HTML.jpg


Fig. 5.5
Papulonodular lichen planus. Acanthosis with sawtooth silhouette, hypergranulosis, lichenoid lymphocytic infiltrate, basal vacuolar change, and dyskeratosis


A313723_1_En_5_Fig6_HTML.jpg


Fig. 5.6
Hypertrophic lichen planus. Epithelial hyperplasia with a thick horny layer

Basal epithelial cells show vacuolization or cytological alterations that can be misinterpreted as atypical, but are secondary to the inflammatory damage. Small subepidermal blisters (Fig. 5.7) can also be observed, in some cases leading to epithelial detachment that is especially prominent in erosive LP (Fig. 5.8). Dyskeratotic apoptotic cells (the so-called Civatte bodies) are usually scarce and their identification often requires a careful search. Direct immunofluorescence (DIF) studies may show shaggy fibrinogen staining of the basement membrane and IgM-positive apoptotic keratinocytes within the basal layer or in the upper portion of the dermis [29].

A313723_1_En_5_Fig7_HTML.jpg


Fig. 5.7
Lichen planus. Small subepidermal blister (Max Joseph space)


A313723_1_En_5_Fig8_HTML.jpg


Fig. 5.8
Erosive lichen planus with epithelial detachment and extensive ulceration


Immunophenotype


The inflammatory infiltrate is fundamentally constituted by T lymphocytes with CD4+, CD8+, and FOXP3+ phenotypes. An increased expression of the proinflammatory cytokines corresponding to Th1 immune response is also present [23].


Differential Diagnosis


The main clinical and histopathological differential diagnosis is to be made with lichen sclerosus (LS). A correct identification of the disease has clinical importance, but it can be difficult because both entities share many clinicopathological features and can even seldom coexist. Nonetheless, there are some helpful clues to tell them apart. The main differential features are summarized in Table 5.1. Vulvar lesions of LP are often painful and their surface is keratotic or ulcerated, instead of itchy and atrophic like in LS. In addition, LP rarely spreads to the vaginal or perianal areas and introital stenosis is a rare event, occurring only in the advanced stages. For patients with extragenital lesions, the distinction between both entities is even easier. Cutaneous involvement is more common in LP than in LS and consists of polygonal flat-top papules, whereas LS is characterized by the development of atrophic macules. Furthermore, oral lesions are frequent in LP but extremely rare in LS, and nail lesions have only been described in LP. Histopathological differentiation between LP and LS in doubtful cases may require a careful study of many step sections; the main feature in favor of LP is the serrated silhouette of the epithelium that, in most cases, is present at least focally. However, to ensure the diagnosis of LP, it is even more important to rule out the presence of distinguishing features of LS, such as basal membrane thickening that can be highlighted by a PAS staining, submucosal edema with ectatic blood vessels, hints of fresh or old hemorrhage, and, principally, the homogeneous hyalinization of the collagen characteristic of LS. Although chronic lesions of LP may show a band of sclerotic collagen at the base, it is never as wide as in LS.


Table 5.1
Main clinical and histopathological differential features between lichen planus and lichen sclerosus







































































 
Lichen planus

Lichen sclerosus

Clinical features

Cutaneous involvement

Frequent

Infrequent

Vaginal involvement

Present, frequent in the erosive variant

Extremely rare

Perianal involvement

Rare

Frequent

Oral involvement

Frequent

Extremely rare

Nail involvement

Infrequent

Absent

Presenting symptoms

Sores and pain

Pruritus

Introital stenosis

Frequent

Only in the advanced stage

Clinical hallmarks

Keratosis and ulceration

Mucosal thinning and hemorrhage

Histologic features

Serrated epidermis

Frequently focal

Extremely rare

Thickening of the basal membrane

Extremely rare

Frequent

Submucosal edema

Extremely rare

Frequent

Ectatic blood vessels

Extremely rare

Frequent

Hemorrhage or siderophages

Rare

Frequent

Collagen hyalinization

Rare

Frequent

Other simulators of LP are the lichenoid drug reactions; their distinction is further complicated by the fact that some drugs can precipitate an LP eruption. The presence of many eosinophils in the infiltrate and sometimes vascular damage can contribute to its recognition. Erosive LP may resemble clinically and microscopically cicatricial pemphigoid and pemphigus. The absence of a significant number of eosinophils and the presence of dyskeratotic cells are features in favor of LP. In case of doubt, a DIF examination can contribute to its distinction. This technique is especially useful in the case of paraneoplastic pemphigus also known as paraneoplastic autoimmune multiorgan syndrome (PAMS). The reason of its utility is that the first manifestations of PAMS can arise in the oral and genital area and they can be microscopically indistinguishable from LP. The presence of immunoglobulins and complement deposition in the intercellular spaces and along the basal membrane of PAMS is definitive to reveal the correct diagnosis.

An international electronic-Delphi consensus on clinicopathological criteria for diagnosis of erosive LP has been recently published [30], but its utility remains to be validated in a large series of cases. The authors propose that three out of the following nine criteria can be sufficient to make the diagnosis of erosive LP:



  • Well-demarcated erosions or erythematous areas at the vaginal introitus


  • Presence of hyperkeratosis and/or Wickham striae at the periphery


  • Symptoms of pain/burning


  • Scarring or loss of normal architecture


  • Vaginal inflammation


  • Involvement of other mucosal surfaces


  • Presence of a well-defined inflammatory band involving the dermoepidermal junction


  • Presence of an inflammatory band consisting predominantly of lymphocytes


  • Signs of basal layer degeneration

A careful clinicopathological correlation is mandatory for a definite categorization of each case, and when reaching a definite diagnosis is not feasible, the best approach is to provide symptomatic treatment and wait for the appearance of more specific findings, rather than trying to fit the case into a wrong entity.


Summary





  • Clinical Presentation



    • Introital erythema extending to the vagina


    • Less frequently hyperkeratosis with Wickham striae


    • Three clinical forms: erosive, papulosquamous, and hypertrophic


  • Histologic Features



    • Band-like lymphocytic infiltrate at the basal epithelial layer


    • Basal cell vacuolization and occasional dyskeratosis


  • Differential Diagnosis



    • Lichen sclerosus


    • Zoon vulvitis


    • Squamous cell carcinoma (hypertrophic variant)


Takeaway Essentials





  • Clinical Relevant Pearls



    • Vaginal involvement favors the diagnosis of lichen planus versus lichen sclerosus.


    • Look for extragenital lesions like lichen planopilaris.


    • The high incidence of autoimmune diseases in these patients makes it advisable to perform a complete workup. Autoimmune thyroiditis is the most frequent among them.


  • Pathology Interpretation Pearls



    • The abundance of plasma cells in the infiltrate can be misleading, but almost always they account for less than 50 % of the cellularity.


    • Isolated atypical squamous cells at the basal layer are often reactive and do not necessarily indicate malignant transformation. Step sections can help to establish or rule it out.



Zoon Vulvitis



Clinical Features


Zoon vulvitis (ZV), also known as plasma cell vulvitis or vulvitis plasmacellularis, is an inflammatory disease quite rare in female and much more frequent in male genitalia [31]. Most cases arise in adult women [32], although ZV has been occasionally reported in prepubertal girls [33]. Some patients are asymptomatic, whereas others present with pruritus that can be intense [34], soreness, pain, burning, or bleeding [32]. Dyspareunia and dysuria are habitual consequences.

Clinically, lesions of ZV tend to occur in the labia minora and introitus and consist of sharply demarcated macules or papules that rarely ulcerate. Their surface is shiny red or brown red. The clitoral glans is rarely involved [32, 3537].

The presence of ZV is not related to other medical disorders, although there are isolated reports of ZV in association with autoimmune polyglandular syndrome [38], LS [39], herpes simplex virus type II [40], and acquired immunodeficiency syndrome (AIDS) [41].


Etiology and/or Pathogenesis


Whereas Zoon balanitis is a clear-cut entity, probably a reactive condition secondary to maceration and chronic irritation in uncircumcised men [31], the existence of its feminine counterpart as an independent entity has been questioned [42]. Nevertheless, vulvar cases with clinicopathological features identical to those in men exist, and the same causes can be accountable as etiological factors, since poor hygiene, sweating, trauma, and persistent friction can also occur in the vulvar mucosa.


Prognosis or Course


In some patients the lesions slowly evolve to spontaneous resolution. For the rest of them, none of the therapeutic approaches that have been tried has provided consistently satisfactory results [37]. The existence of ZV does not carry an increased risk of vulvar SCC.


Histopathology


A plasma cell infiltrate is the hallmark of ZV. However, the infiltrate is not necessarily composed exclusively of plasma cells. Lymphocytes, eosinophils, and neutrophils can also be abundant. A proportion of plasma cells representing 50 % or more of the infiltrate seem to be sufficient for the diagnosis (Fig. 5.9); when the percentage drops to 25–50 %, the coexistence of other characteristic findings of ZV such as epithelial atrophy, vascular proliferation, dilated capillaries, superficial dermal fibrosis, erythrocyte extravasation, and hemosiderin deposition allows recognition of ZV. If plasma cells account for less than 25 % of the infiltrate, a nonspecific plasma cell mucosal reaction cannot be excluded [43].

A313723_1_En_5_Fig9_HTML.jpg


Fig. 5.9
Zoon vulvitis. Inflammatory infiltrate composed mainly of plasma cells. Some lozenge keratinocytes can be appreciated in the left portion of the epithelium

The presence of “lozenge-shaped” or “diamond-shaped” keratinocytes with horizontal axes longer than vertical axes in the suprabasal epithelial layers has been considered a characteristic finding of ZV and balanitis, but this is a rather subjective microscopic finding, and thus its feasibility as a diagnostic clue is questionable.


Differential Diagnosis


Many entities can be included in the clinical differential diagnosis of ZV. Especially important is the distinction from vulvar SCC, Bowen disease, and extramammary Paget disease. A biopsy can easily provide help in this differentiation. Nevertheless, it is important to keep in mind that the presence of areas of mucinous metaplasia has been described in ZV (Fig. 5.10) [44], and care should be taken in not making a wrong diagnosis of extramammary Paget disease. In addition, cases of ZV overlap clinicopathologically with lichen aureus [45]. Other entities included in the differential diagnosis of ZV are lichen planus, contact dermatitis, lupus erythematosus, candidiasis, herpes simplex virus or human papillomavirus infections, bullous disorders, and fixed drug eruption. Especially important is the distinction from syphilis, also characterized by a dense plasma cell infiltrate. The best way to rule out this possibility is performing an immunohistochemical staining against Treponema pallidum; additionally, primary chancres tend to ulcerate, and both primary and secondary syphilis lesions often present with an associated granulomatous infiltrate, plasma cells, vasculitis, and lichenoid or psoriasiform features. ZV in girls may simulate sexual abuse [33], a possibility that at any rate should never be disregarded without further investigation.

A313723_1_En_5_Fig10_HTML.jpg


Fig. 5.10
Zoon vulvitis. Mucinous metaplasia of the superficial epithelium


Summary





  • Clinical Presentation



    • Usually on the labia minora and introitus


    • Shiny red or rusty, sharply demarcated macules or papules


  • Histologic Features



    • Inflammatory infiltrate rich in plasma cells (≥50 % or between 25 % and 50 % with a clinically typical presentation)


  • Differential Diagnosis



    • Syphilis


    • Lichen aureus (overlap cases exist)


Takeaway Essentials





  • Clinical Relevant Pearls



    • Ulceration is rare and more suggestive of syphilis or other conditions.


    • The glans clitoris is almost never involved.


  • Pathology Interpretation Pearls



    • Plasma cells are common in the inflammatory infiltrate of any inflamed mucosa and can obscure the underlying pathology. Before making a diagnosis of Zoon vulvitis, it is necessary to search actively for infections or features that point toward other dermatoses


    • Zoon vulvitis can show mucinous metaplasia that does not indicate extramammary Paget disease.


  • Immunohistochemical Findings



    • An immunostaining with antibodies against Treponema pallidum is the best way to rule out syphilis.


Lichen Sclerosus



Clinical Features


Lichen sclerosus (LS), known in the past as lichen sclerosus et atrophicus or kraurosis vulvae, is a chronic autoimmune mucocutaneous disorder that usually involves the anogenital region of women. It can also occur in male genitalia and extragenital locations. LS is one of the most common vulvar dermatoses [14], with a predilection for Caucasian females with two peaks of incidence in prepubertal and postmenopausal women. The prevalence of vulvar LS has been reported to be 0.11 % for girls [46] and 1.7 % for adult women [47].

Lesions of LS usually begin around the clitoris with secondary involvement of the interlabial sulcus (Fig. 5.11) and posterior spread to the labia minora and majora, the perineum, and the perianal skin (Fig. 5.12), with a typical eight-shaped figure. In contrast with LP, vaginal involvement in LS is extremely rare [48], but episiotomy scars and areas with genital jewelry can be involved due to a Koebner phenomenon. Extragenital lesions may develop in up to 11 % of patients [49, 50].

A313723_1_En_5_Fig11_HTML.jpg


Fig. 5.11
Lichen sclerosus. The clitoris and interlabial sulcus showing erythema, mucosal thinning, focal pigmentation, and a small fissure (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)


A313723_1_En_5_Fig12_HTML.jpg


Fig. 5.12
Lichen sclerosus. Lesion involving the vulva, perineum, and perianal skin (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)

Vulvar soreness and itching are the commonest symptoms in girls. Adult patients may also report burning sensation or pain, and dyspareunia and dysuria are common complaints, especially when fissures and ulcers develop.

On clinical examination, the earliest changes include erythema, mucosal thinning and wrinkling, focal lichenification, erosion, purpura, abnormal pigmentation, and hypotrichosis (Fig. 5.11) [51]. Later on, mucosal pallor, atrophy, or hyperkeratosis becomes more evident, and pale indurated papules and plaques with areas of telangiectasia and hemorrhage develop (Figs. 5.12 and 5.13). In the advanced stage, the lesions are lichenified white-porcelain papules and plaques with superficial crinkling or cellophane-like atrophic skin (Figs. 5.14 and 5.15). Ulcerations, fissures, blisters, ecchymoses, and subepidermal hemorrhage are frequent (Figs. 5.11 and 5.12) [51]. Chronic inflammation may lead to scarring with adhesions of the clitoral hood, resorption and fusions of the labia minora, pseudocyst formation, and stenosis of the vaginal introitus. Since there is no synchronicity among the individual lesions of LS, areas with early and late changes can occur simultaneously in different vulvar zones from the same patient [52].

A313723_1_En_5_Fig13_HTML.jpg


Fig. 5.13
Lichen sclerosus. Atrophic mucosa with telangiectasia and hemorrhage (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)


A313723_1_En_5_Fig14_HTML.jpg


Fig. 5.14
Lichen sclerosus. Intense atrophy with indurated white-porcelain areas (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)


A313723_1_En_5_Fig15_HTML.jpg


Fig. 5.15
Lichen sclerosus. Atrophic mucosa with multiple erosions (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)

The typical dermoscopic features of LS include patchy structureless white to yellowish areas, linear anastomosing telangiectasia, and randomly arranged red dotted areas corresponding to loose aggregates of blood vessels [53].

Autoimmune disorders are frequent in patients with LS [19, 54]; they have been reported to be present in at least 18.9 % of cases [54]. This association is less common in the male population with genital LS. In two case series autoimmune thyroiditis was the most frequent autoimmune comorbidity, occurring in 12–16 % of patients; vitiligo was the second most frequent in one of the studies [19], whereas morphea represented only 1.5–1.7 % of the associated autoimmune disorders.

LS has been considered to carry an increased risk of developing vulvar SCC in adult patients [55, 56]. In a cohort of symptomatic vulvar LS patients, malignant transformation was described in 21 % of cases [56]. Nevertheless, the mechanisms and real incidence of malignant transformation are subject to debate. Some authors contend that even though atypical epithelial changes are frequently found in close contact to invasive SCC [55, 57], only a small proportion of them are typical areas of LS, whereas most cases correspond to differentiated vulvar intraepithelial neoplasia (dVIN) [58], a nonhuman papillomavirus (HPV)-related dysplasia that mainly affects elderly patients [59]. In summary, even though LS has been considered a potential precursor of dVIN, the risk of LS malignant transformation might have been overestimated. A counterargument underscores the possibility of asymptomatic LS patients and complete replacement of a precursor lesion by tumor as potential reasons to consider the reported incidence of malignant transformation an underestimate.

Abnormal pigmentation is frequent in LS, the most common alterations being melanosis and lentiginosis [60]. Melanocytic nevi occurring in areas of LS may acquire features of persistent melanocytic nevi and lead to a misdiagnosis of malignant melanoma, especially in children [61]. However, rare cases of malignant melanoma associated with vulvar LS have been reported in the literature [62, 63], and in the presence of atypical pigmented areas, a biopsy is mandatory [64].

There are also individual reports of Langerhans cells histiocytosis, basal cell carcinoma, and Merkel cell carcinoma [64, 65] appearing in the setting of LS.


Etiology and/or Pathogenesis


Autoimmunity and genetic factors play a major role in the development of LS. On one side, the high incidence of familial cases and the association with several HLA haplotypes favor the existence of an inherited susceptibility [66]. On the other side, the close association between LS and autoimmune diseases demonstrated by several studies [54, 67] and the existence of autoimmune antibodies in 42 % of LS patients [67] strongly support autoimmune mechanisms. Furthermore, the inflammatory infiltrate in LS displays an autoimmune phenotype corresponding to a Th1 response with high expression of microRNA-155, like in LP [18]. Another interesting observation in this regard is the presence of IgG circulating autoantibodies against extracellular matrix protein 1 (ECM1) in approximately 75 % of patients with vulvar LS [68], whereas these antibodies are absent in patients with other lichenoid dermatoses [68]. Furthermore, mutations in the ECM1 gene are responsible for lipoid proteinosis, which presents histopathological similarities with LS; this has led some authors to suggest that ECM1 could act as an autoantigen [68]. However, recent studies have shown that the autoreactivity to this antigen increases with the progress and extent of the disease, indicating that it is a secondary pathogenetic event that probably contributes to LS progression, rather than being involved in the initiation of the process [69]. Furthermore, high titers of autoantibodies targeting the basement membrane zone have been found in several studies [70, 71]. This finding has not been confirmed using more accurate detection techniques [71]. Nevertheless, a relationship seems to exist, at least in some cases, between LS and immunobullous diseases [72].

Another element that might facilitate the development of LS would be chronic exposure to urine of a susceptible epithelium under occlusion or an alteration of the epithelial barrier, as in atopic dermatitis [73, 74]. Hormonal factors might also influence the development of the disease, since in a series of 44 pediatric cases, both Turner syndrome (2 cases) and renal disease (2 cases) were overrepresented [75]. Finally, the altered methylation and hydroxymethylation status present in vulvar LS (either isolated or associated with vulvar SCC) may contribute to enhance the autoimmune and inflammatory response [76, 77], whereas the influence of infectious agents remains uncertain [60].


Prognosis or Course


The disease can be progressive or follow a relapsing and remitting course [60]. There is no correlation between the duration of the disease, the degree of clinical and histopathological involvement, and the severity of symptoms [52, 60]. In a large series of newly diagnosed LS in adult women, up to 58 % of cases were asymptomatic, although in many patients some scarring of the clitoral prepuce or resorption of the labia minora was clinically evident [47].

Most remissions occur in the first 3 months after treatment [62]. Spontaneous healing is rare, even in prepubertal cases where there can be some improvement with age, but resolution is especially unlikely if the disease remains active after menarche [78, 79].


Histopathology


The typical appearance of a fully developed lesion of LS shows mucosal atrophy with vacuolar degeneration at the basal layer, basal membrane hyalinization (Fig. 5.16), and occasional dyskeratosis. Subepithelial edema is commonly present and can be so intense as to cause pseudo-vesiculation. The edema merges imperceptibly with the dermal collagen, which shows a characteristic homogeneous ground-glass appearance (Fig. 5.17). This sclerotic collagen forms a wide band as the lesion progresses, entrapping dilated capillary vessels (Fig. 5.18) that bleed easily. An inflammatory infiltrate of variable intensity is often present at the interface between the altered collagen and the uninvolved connective tissue. Hair follicles with corneal plugs, dystrophic hairs, and hyperkeratotic acrosyringia can also be observed at this stage (Fig. 5.19).

A313723_1_En_5_Fig16_HTML.jpg


Fig. 5.16
Lichen sclerosus. Hyalinization at the basal membrane zone and intense subepithelial edema


A313723_1_En_5_Fig17_HTML.jpg


Fig. 5.17
Lichen sclerosus. Homogeneous sclerosis of the collagen in the upper dermis with superficial edema


A313723_1_En_5_Fig18_HTML.jpg


Fig. 5.18
Lichen sclerosus. Hyalinized collagen containing dilated capillary vessels


A313723_1_En_5_Fig19_HTML.jpg


Fig. 5.19
Lichen sclerosus. Epithelial atrophy with keratin plugs

Unlike in advanced stages, the earliest changes of LS are subtle and can be easily missed or misleading. The epithelium may display psoriasiform hyperplasia and the lymphocytic infiltrate can be dense or sparse, with lichenoid, interstitial, epitheliotropic, or vasculitic pattern (Fig. 5.20) [80, 81]. When the sclerosis is still not prominent, the absence of cytological atypia at the lower epithelial layers helps to rule out dVIN [82]. The key for diagnosis at this early stage can be found looking for the typical features of LS around the adnexal structures, where the lesion is more evident.

A313723_1_En_5_Fig20_HTML.jpg


Fig. 5.20
Lichen sclerosus. Focus of early involvement showing a lichenoid pattern with lymphocytic infiltrate obscuring the basal layer, hypergranulosis, and hyperkeratosis. In close contact with this area, the biopsy shows features of advanced stage with the characteristic hyaline sclerosis of the collagen

Lichenification due to chronic scratching can modify the usual appearance of LS with epithelial acanthosis, presence of dyskeratotic cells in all layers of the epidermis, hypergranulosis, and hyperkeratosis that can be compact and orthokeratotic or parakeratotic [82]. Some cases show large areas of subepithelial hemorrhage. The accumulation of melanophages as a result of basal destruction is rarely prominent, but in some instances can cause areas of striking atypical pigmentation. Aggregates of elastotic material can be also found. Mucinous metaplasia is another rare finding and has to be differentiated from Paget disease [83].


Immunophenotype


Lymphocytes present within the infiltrate are mostly T cells, CD4+, CD8+, and FOXP3+ cells [18]. Overexpression of MIB1 and p53 may help to identify cases with higher risk to evolve to vulvar SCC [84], but p53 immunoreactivity involving only the basal cell layer can also occur in LS due to ischemic stress [85].


Differential Diagnosis


Sexual abuse is the main clinical differential diagnosis in girls. In one study this possibility was considered in 77 % of pediatric cases. Nevertheless, this possibility has to be always considered since both conditions may coexist [86]. The earliest clinical changes in adults can be subtle and simulate vitiligo or Candida infection. In more advanced stages the differential diagnosis includes LP, dVIN, lichen simplex chronicus, psoriasis, mucosal pemphigus, cicatricial pemphigoid, extramammary Paget disease, and vulvar SCC [60, 80, 87]. Vaginal involvement does not rule out LS, but is strongly in favor of other possibilities [48].

Histopathologically the main differential diagnosis is lichen planus. The most important differential features between the two entities are summarized in Table 5.1. It is also important to differentiate LS from dVIN; even though both diseases can coexist in the same patient, the latter should be diagnosed only in the presence of obvious basal atypia. Some cases with prominent blistering may simulate pemphigoid, and the presence of epithelial atrophy with a lymphocytic infiltrate at the dermoepidermal junction and rows of lymphocytes within the basal layer of the epidermis may resemble early lesions of mycosis fungoides (MF). A differential feature is the presence of homogenized collagen in LS, whereas in MF the dermis contains coarse bundles of collagen. Nonetheless, such an important differential diagnosis cannot be solely based on this inconstant feature. Furthermore, in some cases it may be necessary to study step sections looking for the typical features of LS, or even perform additional biopsies from different areas, in order to clarify the diagnosis. An additional obstacle for the distinction is that in a single biopsy from early MF, neither the immunophenotype, nor a clonal T cell receptor gene rearrangement (TCR) are reliable techniques to separate benign from malignant infiltrates.

Loss of dermal elastic fibers in LS but not in LP has been proposed as a clue for their distinction [88], but subsequent studies have failed to confirm these differences [89].

Overexpression of p53 and MIB1 contributes to the identification of lesions with high risk of vulvar SCC transformation [84]. However, the prognostic implications are not conclusive when p53 expression is limited to the basal layer [85]. Additionally, alterations in the basal membrane can be highlighted using periodic acid-Schiff (PAS) staining, which at the same time allows ruling out Candida infection.


Summary





  • Clinical Presentation



    • Early lesions: erythema and mucosal thinning on the clitoris and interlabial sulcus


    • Late lesions: white-porcelain papules and plaques with cellophane-like atrophic skin and figure-of-eight distribution (complete vulvar involvement, narrowed at the perineum and surrounding the anal region)


  • Histologic Features



    • Mucosal atrophy with vacuolar damage


    • Edema between the epithelium and a band of sclerotic “glassy” collagen


  • Differential Diagnosis



    • Lichen planus


    • Differentiated VIN


Takeaway Essentials





  • Clinical Relevant Pearls



    • Look for extragenital lesions (present in 11 % of cases).


    • The high incidence of autoimmune diseases in these patients makes it advisable to perform a complete workup. Autoimmune thyroiditis is the most frequent among them.


  • Pathology Interpretation Pearls



    • In the early lesions look for typical changes around adnexal structures.


    • In a small or fragmented biopsy specimen, basement membrane hyalinization is a clue for the diagnosis of lichen sclerosus.


    • Melanocytic nevi within the lesion can acquire features that simulate melanoma.


    • For vulvar lesions resembling early mycosis fungoides, consider the diagnosis of lichen sclerosus and look for its typical features performing additional sections, if necessary, or ask for a new biopsy from a different area.


  • Histochemical Findings



    • A PAS staining can highlight the basal membrane thickening.


    • A staining for elastic fibers can illustrate the absence of elastic fibers at the base of the lesions that, although nonspecific, points toward the diagnosis of lichen sclerosus.


  • Immunohistochemical Findings



    • Overexpression of p53 limited to the basal layer can be reactive and does not indicate dVIN.



Granulomatous Diseases



Crohn Disease



Clinical Features


Crohn disease (CD) is a chronic relapsing granulomatous disorder that can affect any portion of the gastrointestinal tract. It is characterized by transmural bowel inflammation with marked tendency to form fistulas to adjacent structures and sometimes to the skin [90]. Mild gynecological alterations can occur in up to 24 % of female patients [91] since pediatric age [92], but serious gynecological complications such as fistulas or metastatic CD are less frequent. In a series of patients with CD, genital fistulization was present in 3.8 % of women; in most cases the site of drainage was the vagina and less frequently the vulva [93]. Conversely, the vulva is the gynecological location most susceptible to develop metastatic CD [94], defined as the presence of non-caseating granulomatous inflammation discontinuous to gastrointestinal tract involvement. Metastatic and intestinal CD may occur simultaneously; nonetheless, metastatic lesions can also precede or appear subsequently to intestinal involvement [91]. More than half of metastatic CD cases occur in gynecological locations [95]; the average age of presentation is 34 years, but there are reports in children as young as 8 years old [96, 97].

The commonest clinical manifestations of CD in the vulva are local edema with labial swelling, ulcerations (that tend to be linear but can adopt other configurations) [97, 98], abscesses, draining sinuses, and hypertrophic exophytic lesions with a “bulbous” or condylomatous appearance (Fig. 5.21) [95, 97101]. An increased incidence of malignancies has also been reported [98].

A313723_1_En_5_Fig21_HTML.jpg


Fig. 5.21
Crohn disease. Vulvar edema associated with linear erythematous lesions in the inguinal region and a bulbous perianal protuberance (Courtesy of Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Badalona, Spain)


Etiology and/or Pathogenesis


The exact pathogenesis of metastatic CD is not known, but the dysregulated proinflammatory response has been classically attributed to the migration to the skin of intestinal antigens or immune complexes, probably related to the gut microbial flora [102].


Prognosis or Course


The severity of non-intestinal manifestations of CD may not parallel the intestinal disease [90], but many metastatic lesions resolve spontaneously or with the same treatment used for the control of the intestinal process [103]. Nevertheless, surgical repair can be required due to delays or failure of medical treatment.


Histopathology


Fistulization of Crohn disease can be easily diagnosed on clinical grounds alone, but a biopsy may be required to rule out malignant transformation. Non-caseating granulomas have been considered the most distinctive feature of metastatic CD (Fig. 5.22). In some cases these granulomas are well developed, with presence of multinucleated giant cells of Langhans and foreign body types [94, 104], but this is not a constant feature; definite granulomas were present in only 38 % of cases in a series of vulvar CD [98]. Thus, relying exclusively in this criterion would utterly impair the sensitivity of microscopic diagnosis. In the same series granulomas were not always well developed, and ulceration was observed in the same proportion as granulomatous inflammation [98]. Two other findings that have been described in metastatic CD are the combination of lichenoid and granulomatous dermatitis and the presence of granulomatous vasculitis (Fig. 5.23) [94]. Dilated lymphatic spaces were observed by Foo et al. [98] in 31 % of biopsy specimens, leading in some cases to an initial diagnosis of lymphangioma or lymphangiokeratoma. It has been hypothesized that lymphatic ectasia and proliferation might appear as a consequence of the fibrosis due to surgical procedures or chronic inflammation [98]. Remarkably, an image similar to an intralymphatic histiocytosis can be appreciated in one paper [105], in which it was labeled as lymphangitis. The presence of aggregates of neutrophils and focal eosinophilia (Fig. 5.22) is also a feature typical of CD, and necrobiosis (Fig. 5.23) is an additional finding that favors this diagnosis.

A313723_1_En_5_Fig22_HTML.jpg


Fig. 5.22
Crohn disease. Granulomatous inflammation with multinucleated giant cells. Eosinophils are noticeable


A313723_1_En_5_Fig23_HTML.jpg


Fig. 5.23
Crohn disease. Granulomatous vasculitis and focus of necrobiosis


Differential Diagnosis


The clinicopathological differential diagnosis of vulvar CD includes hidradenitis suppurativa that may cause draining sinuses and areas of abscessification. Hidradenitis can be differentiated from CD because of the abundance of neutrophils with a tendency to abscessification and the likelihood of the infiltrate to be centered in the apocrine glands and hair follicles. Cystic hair follicles are also frequent, as well as epidermal cysts. It is common to find areas of granulomatous reaction, but it tends to be foreign body type, secondary to keratin leakage from the ruptured cysts.

Pyoderma gangrenosum (PG) is a neutrophilic autoinflammatory dermatosis that frequently occurs in relation with systemic processes, with inflammatory bowel disease being one of the most common triggering factors. Genital involvement by PG in a patient with CD is rather unusual, but this has to be considered in the differential diagnosis of metastatic CD [106]. Microscopically, well-developed lesions of PG are characterized by neutrophilic infiltrate that is in general more suppurative than vulvar CD. In addition, in PG the granulomatous inflammation is always necrotizing and foci of neutrophilic or lymphocytic vasculitis can be found.

Infections should also be differentiated from vulvar CD. The most important are tuberculosis, actinomycosis, and lymphogranuloma venereum. Clinically, the coexistence of perianal lesions such as skin tags, anal fissures, ulcers, fistulas, perianal abscesses, and anorectal strictures favors the diagnosis of vulvar CD. In addition, the absence of pain or tenderness in the vulvar swelling militates against an infectious etiology [107]. In tuberculosis the granulomas are noticeable, confluent, and caseating. In actinomycosis the main microscopic finding is the presence of fistulous tracts filled by neutrophilic infiltrate that usually contain large collections of actinomyces. The hallmark of lymphogranuloma venereum is the presence of lymphadenopathies that can contain stellate areas of necrosis leading to draining sinuses and their complete destruction. Microscopically, the dermal findings are usually nonspecific, and the main involvement is located in the subcutaneous tissue where the lymph nodes can be completely effaced due to the necroinflammatory process. In case of doubt, histochemical, immunohistochemical, and molecular techniques, as well as microbiological cultures, are advisable to rule out an infectious process.

Vulvar sarcoidosis can also be considered in the differential diagnosis of CD; the presence of an abundant inflammatory infiltrate rich in plasma cells and eosinophils, ulceration, and lymphatic dilatation are features that favor the diagnosis of CD. Vulvitis granulomatosa is the genital counterpart of cheilitis granulomatosa and can overlap with metastatic CD [108], but cases unrelated to CD also occur and this possibility should be taken into consideration.

Finally, factitial dermatitis and sexual abuse can also simulate a vulvar CD. In both cases the lesions are often externally initiated; superficial excoriations are the most common finding, and, in general, the inflammatory infiltrate is limited to the tissues closer to the area of where the injury was inflicted. The remaining tissues are free of pathology although sometimes they may show scars or hints of previous involvement. However, it is important to keep in mind that the damage can be caused by a wide range of means such as the suction effect, thermal injuries, or injection of foreign materials and, therefore, can lead to a host of inexplicable changes. Thus, factitial dermatitis and sexual abuse are possibilities that always have to be taken into consideration when facing unusual clinicopathological findings. The main differential features among CD, granulomatous infections, foreign body reactions, and sarcoidosis are summarized in Table 5.2.


Table 5.2
Granulomatous diseases of the vulva






































































































 
Metastatic Crohn disease

Sarcoidosis

Foreign body reaction

Granulomatous infections

Vulvar clinical presentation

Edema

Pruriginous patches, papules, or nodules

Erythema and tumefaction

Swelling

Ulceration

Ulceration is rare

Ulceration

Draining sinuses

Abscessification

Exophytic lesions

Local pain

Moderate

Rare (one case)

Moderate

Usually intense

Associated clinical findings

Anal fissures and exophytic lesions

Simultaneous inguinal, perineal, and perianal involvement

Related to the foreign body origin (such as recent surgery or a neoplasm)

Fever

Gastrointestinal symptoms

Malaise

Facial lesions

Systemic involvement

Epidermis

Frequently ulcerated

Rarely ulcerated

Usually normal

Variable:

 Normal

Occasional lichenoid features

 Ulceration

 Epidermal hyperplasia with parakeratosis

Dermis

Granulomatous dermatitis with mixed cell inflammatory infiltrate

Non-necrotizing granulomas with scant tendency to fuse

Palisades of mononucleated histiocytes and multinucleated giant cells

Necrotizing granulomas

Small abscesses of neutrophils

Sparse lymphocytic infiltrate and absence of acute inflammation

Foreign material in the center of the granulomas or within the cytoplasm of giant cells

Neutrophils and plasma cells depending on the type of infection

Type of granulomas

Necrotizing and non-necrotizing

Sarcoid

Foreign body type

Necrotizing

Hallmark

Granulomatous inflammation with ulceration

Non-necrotizing epithelioid granulomas that do not tend to fuse

Granulomas with multinucleated foreign body-type giant cells

Necrotizing granulomas

Non-caseating granulomas in more than one-third of cases

Scant lymphocytic infiltrate

Nonconstant additional microscopic findings

Eosinophils

Scar tissue and foreign bodies can trigger sarcoidosis and can be focally identified

Eosinophils

Infectious agents. Usually identified with the contribution of special techniques

Granulomatous vasculitis

Abscesses of neutrophils

Dilated lymphatic spaces

Fibrosis

Necrobiosis


Foreign Body Reaction



Clinical Features


Foreign body reactions appear clinically as localized areas of tumefaction and erythema. The most common causes in the vulva are keratinous material released to the interstitium by a follicle-associated process and the rupture of an epidermal inclusion cyst. Other possible causes are the presence of retained suture material from a previous surgical procedure and the existence of tattoos and genital jewelry. Much rare is the accidental implantation of sand, splinters, and other materials or the anecdotal cases of migration of liquid silicone injected in the breasts or buttocks for augmentation purposes [109]. Extensive talcum powder use to mitigate pruritus can produce foreign body granulomas; histologic study and directed clinical history can clarify this diagnosis [110]. Another rare cause of foreign body reaction is the presence of inert extracellular material that originated from a neoplasm, such as keratin from a cystic teratoma or mucopolysaccharides from an adenocarcinoma or a myxoid neoplasm [111].


Summary





  • Clinical Presentation



    • Local edema with labial swelling


    • Ulceration (often linear), abscesses, and draining sinuses


    • Exophytic swollen lesions, especially perianal


  • Histologic Features



    • Non-caseating granulomas or mixed granulomatous infiltrate with eosinophils


    • Lichenoid and granulomatous dermatitis with vascular damage


  • Differential Diagnosis



    • Hidradenitis suppurativa


    • Sarcoidosis


    • Infections


Takeaway Essentials





  • Clinical Relevant Pearls



    • Anal lesions, even fissures or skin tags, should alert about the possibility of vulvar Crohn disease.


    • Vulvar Crohn disease can be the first manifestation of the process (also in children). Nevertheless, endoscopy can detect asymptomatic gastrointestinal involvement and aid in confirming the diagnosis.


  • Pathology Interpretation Pearls



    • Granulomas are not always well formed; frequently CD presents as a loose collection of histiocytes.


    • Dilated lymphatic spaces can be misinterpreted as tumoral or malformative lesion, yet they are a clue for diagnosis.


Histopathology


The typical histologic appearance in all cases is that of a foreign body reaction with mononucleated macrophages that tend to form palisades around the causative material and/or foreign body-type multinucleated giant cells that may contain phagocytosed foreign materials in their cytoplasm; eosinophils and neutrophils can be abundant (Fig. 5.24). Examination under polarized light microscopy is recommended to highlight the foreign material and can contribute to its identification, as in the case of talcum powder, which displays a characteristic Maltese cross appearance.

A313723_1_En_5_Fig24_HTML.jpg


Fig. 5.24
Foreign body reaction. A giant cell containing phagocytosed surgical material and many eosinophils in an area of induration developed after a gynecological surgical procedure


Differential Diagnosis


The differential diagnosis includes other granulomatous vulvar processes such as CD or sarcoidosis; granulomatous infections, especially granuloma inguinale, and deep fungal infections; and primary immunodeficiencies. Granulomas in sarcoidosis and CD can contain occasional multinucleated giant cells, but never as numerous as in a foreign body reaction. Palisades of histiocytes are also absent in both processes, and although small fragments of foreign material can be occasionally detected in the cytoplasm of giant cells, they are not present in a significant degree, but rather as an incidental finding.

Granulomatous infections including tuberculosis, deep mycosis, and granuloma inguinale should be ruled out. In tuberculous granulomas giant cells are mostly Langerhans cell type and necrosis is caseous. Deep mycotic infections are characterized by the association of granulomas and abscesses of neutrophils, similar to foreign body reaction. The cause can be the accidental implantation of a splinter or any other contaminated foreign material, making a PAS staining mandatory to exclude this possibility. Vulvar lesions of granuloma inguinale are often ulcerated and the infiltrate contains many plasma cells in addition to numerous histiocytes. These histiocytes often contain many elements of Klebsiella granulomatis (Donovan bodies) in their cytoplasm that are better appreciated using a Giemsa staining.

In primary immunodeficiencies, there is not only an increased risk of infections but also relapsing episodes of noninfectious chronic granulomatous inflammation. Bacterial, fungal, or viral tests on the skin biopsy are often helpful to exclude an infection. The main differential features among CD, granulomatous infections, foreign body reactions, and sarcoidosis are summarized in Table 5.2.

Only gold members can continue reading. Log In or Register to continue

Nov 11, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Inflammatory Dermatoses Affecting the Dermis or Both the Epidermis and Dermis of the Vulva
Premium Wordpress Themes by UFO Themes
%d bloggers like this: