Vulvar dystrophies

Inl J Gynecol Ohsret, 1991, 35: 269-213 International Federation of Gynecology

269 and Obstetrics

Vulvar Dystrophies* ACOG Technical Bulletin Number 139 The vulvar dystrophies (nonneoplastic epithelial disorders of the vulvar skin and mucosa) are seen frequently in clinical practice. These disorders can be classified into those demonstrating squamous cell hyperplasia, lichen sclerosus, and a variety of other dermatoses. The term “chronic vulvar dystrophies” has been introduced for the entire group of lesions known in the past as “leukoplakia,” “leukoplakic vulvitis,” “lichen sclerosus et atrophicus,” “kraurosis vulvae,” “primary atrophy,” “sclerotic dermatosis,” and “atrophic and hyperplastic vulvitis” (1). In the 1960s it was suggested that the different terms used by the gynecologist and the dermatologist applied to a variation in the epithelial response of the vulva to one or more adverse agents (1). It was believed that the special appearance of the response of the vulvar skin is explained by its warm, moist environment. Differences in the appearances of vulvar skin do not necessarily indicate separate diseases; rather, they are the environmentally conditioned reactions to adverse agents, whatever those may be. In support of this suggestion, evidence has been cited that, if the involved vulvar skin is excised and normal skin is transplanted from a site not ordinarily subject to lesions characteristic of the vulvar area, the grafted epithelium undergoes the same changes that occur in the original vulvar skin before its removal (2). Because of confusion surrounding the terms used to describe vulvar diseases, in January 1975, the InternationalSocietyfortheStudyofVulvarDisease(ISSVD) adopted the following classification of the dystrophies, based on the histopathologic features of the lesions, which it hoped would be readily understood by both clinicians and pathologists: I. Hyperplastic dystrophy A.Without atypia B.With atypia *The committee

wishes to thank

January 1990 II. Lichen sclerosus III. Mixed dystrophy-lichen hyperplasia A.Without atypia B.With atypia

sclerosus with epithelial

This classification has been widely accepted and has resulted in an accumulation of comparable data from many institutions, allowing clinicians to obtain a better understanding of the natural history of these disorders. There have, however, been many practical objections to this classification. For example, lesions demonstrating atypia probably do not belong within the classification of nonneoplastic epithelial disorders, since their natural history is entirely different from lesions that do not demonstrate cellular atypia. Furthermore, many experienced dermatologists and gynecologists feel that the lesions classified as “mixed dystrophy” are actually lichen sclerosus with areas of reactive epithelial hyperplasia. The areas of hyperplasiamay represent the response of the epithelium to chronic scratching. In addition, the majority of lesions classified as “hyperplastic dystrophy”probably represent variants of lichen simplex chronicus (dermatitis associated with chronic itching and scratching). For these reasons, at the 1987 meeting of the ISSVD, a modified classification was proposed. This classification has received the general acceptance of gynecologists, dermatologists, and pathologists, as well as a number of authoritative intemational organizations. Unlike the prior classification, which was based purely on histopathologic features of the lesions being studied, the following classification is based upon a combination of gross and histopathologic changes: Nonneoplastic Epithelial Disorders of the Vulvar Skin and Mucosa I. Squamous cell hyperplasia (formerly hyperplastic dystrophy)

Raymond

H. Kaufman,

MD, for his assistance

in the development

of this bulletin.

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II. Lichen sclerosus III. Other dermatoses Squamous cell hyperplasia includes lesions with no known cause. Lichen sclerosus with associated squamous cell hyperplasia was formerly classified as a mixed dystrophy. When these two disorders are associated, the current recommendation is to report both lichen sclerosus and squamous cell hyperplasia. Mixed epithelial disorders may also be associated with cellular atypia (vulvar intraepithelial neoplasia). When this occurs, each diagnosis shouldbe reported (eg, vulvarintraepithelial neoplasia I-III; lichen sclerosus). Since a distinction between epidermal thickening and thinning, as well as the presence of atypia, is not always possible by gross inspection, the classification of a lesion also requires evaluation of its microscopic characteristics. The histopathologic appearance, like the gross appearance, may vary in different sites of the vulva; thus, under some circumstances, lesions can be accurately classified only if biopsies are taken from several locations. Other dermatoses, such as lichen planus and psoriasis, encompass a large, diverse group of disorders that are outside the scope of this bulletin.

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Cell Hyperplasia (tlyperplastic

Most hyperplastic lesions represent lichen simplex chronicus. Although these lesions are associated with epithelial thickening and hyperkeratosis, their gross appearance is highly variable. Moisture, scratching, and medications may cause variations in the appearance of lesions in the same patient. The areas of the vulva most frequently involved include the labiamajora, intralabial sulci, outer aspects of the labia minora, and clitoris. Changes may also extend to the lateral surfaces of the labia majora or beyond. Areas of squamous cell hyperplasia are often localized, elevated, and well delineated. On other occasions, vulvar lesions may be extensive and poorly defined. The vulva may have a dusky-red appearance when the degree of hyperkeratosis is slight. At other times, welldefined, white patches may be seen, or a combination of ted and white areas may be observed in different locations. Thickening, fissures, and excoriations may result from chronic scratching and require careful evaluation,

since carcinoma may first be exhibited by these features. Biopsy reveals a variable increase in thickness of the horny layer (hyperkeratosis) and irregular thickening of the malpighian layer (acanthosis). The latter produces a thickened epithelium, as well as lengthening and distortion of the rete pegs. Parakeratosis may also be present. The granular layer of the epithelium is usually prominent. The papillae become conspicuous and are often edematous. An inflammatory reaction is apparent within the dermis, and varying numbers of lymphocytes and plasma cells are seen.

lichen Sclerosus Most lesions interpreted in the past as kraurosis vulvae, primary atrophy, and the atrophic phase of leukoplakia are examples of lichen sclerosus. Henri Hallopeau first described this lesion in 1887, terming it “lichen planus atrophicus.” Lichen sclerosus represents a specific disease that is often found in nongenital sites. The Nomenclature Committee of the ISSVD has recommended that the “et atrophicus” be dropped from “lichen sclerosus.” Some studies have suggested that the epithelium in lichen sclerosus is metabolically active, rather than atrophic (3,4). It has been observed that involucrin, a precursor of the envelope protein in human stratum comeum, was present throughout the entire epithelium except for the basal layer in 19 of 27 slides of lichen sclerosus (5). The presence of involucrin reflects cellular differentiation, and its presence in all layers except the basal layer in lichen sclerosus suggests early differentiation of the squamous cells, which couldexplain the apparent thinness of the epidermis. In well-developed classical lesions, the skin of the vulva has a crinkled (“cigarette-paper”) or parchmentlike appearance that commonly extends around the anal region in a figure-eight or keyhole configuration. At other times, the changes are localized, often in the periclitoral area or perineum. Edema of the clitoral foreskin may completely hide the clitoris. Phimosis of the clitoris may be seen late in the course of the disease. The labia minora almost completely disappear as a result of atrophy. Synechiae may develop between the edges of the skin in these locations, causing pain and limited physical activity. Fissures may also develop in natural folds of the skin and in the posterior fourchette. The introitus may become so stenotic that it barely

A COG Technical Bulletin

admits one finger. Small hematomas and areas of telangiectasia may be noted within the skin and mucosa. In children, the vulvar changes are essentially the same as those noted in the adult. Occasionally, a vesicular, bullous, edematous lesion may be seen in a child. The microscopic features of lichen sclerosus include hyperkeratosis, epithelial thinning with flattening of the rete pegs, cytoplasmic vacuolization of the basal layer of cells, and follicular plugging. Beneath the epidermis is a zone of homogenized, pink-staining, collagenous-appearing tissue that is relatively acellular. Edema is occasionally seen in this area. There is an absence of elastic fibers. Immediately below this zone lies a band of inflammatory cells consisting of lymphocytes and some plasma cells. Lichen sclerosus is often associated with foci of both hyperplastic epithelium and thin epithelium (formerly “mixed dystrophy”). During extended periods of observation and medical treatment, the vulva may undergo grossly conspicuous changes. Areas of hyperplasia may develop adjacent to otherwise atrophicappearing tissue or may be seen mixed with atrophic areas within otherwise classical-appearing lichen sclerosus. These changes are probably caused by scratching and may represent a reactive hyperplasia of the epithelium. Under these circumstances, microscopic study of the specimens from the vulvar lesions will verify the coexistence of hyperplastic and atrophic changes. Squamous cell hyperplasia has been found in 27-35% of women with lichen sclerosus (6,7). Approximately 5% of patients with lichen sclerosus were also found to have intraepithelial neoplasia (6).

Etiology The pathogenesis of nonneoplastic epithelial disorders of the vulva remains obscure. The environment of the vulva influences the pathologic processes, but the specific roles of chronic trauma, allergy, nutritional deficiency, psychoneurosis,metabolic disturbance, andother factors are unknown. There appears to be a relationship between chronic vulvovaginal infections, such as candidiasis, and lichen simplex chronicus, particularly in diabetics. Scratching in one location may produce a dermatitis that meets all the criteria of lichen simplex chronicus.

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Topical testosterone benefits many individuals with lichen sclerosus, although the reasons for its effectiveness are not clear. In patients with untreated vulvar lichen sclerosus, serum levels of free testosterone and androstenedione were found to be significantly increased compared with normal values for age, whereas those of dihydrotestosterone were significantly decreased (8). Dihydrotestosterone levels rose and exceeded normal values after topical testosterone therapy. These results suggest that decreased enzymatic activity (5a-reductase), which converts testosterone to the active form dihydrotestosterone, may be partially responsible for this disease. An association between lichen sclerosus and autoimmune disease has also been suggested by several studies in which higher frequencies of autoimmunerelated disease and autoantibodies have been reported (9-l 1). Studies of the antigens of the human lymphocyte antigen system in patients with vulvarlichen sclerosus have shown conflicting evidence regarding the distribution of tissue types between these patients and the general population (12). Finally, increased activity of the proteolytic enzyme elastase has been demonstrated in lichen sclerosus (13). Thus, fibrous tissue may not be destroyed at the normal rate and may account for the collagen deposition in this disease.

Relationship to Cancer One of the most controversial points about the nonneoplastic epithelial disorders of the vulva is their malignant potential. The likelihood that a superimposed vulvar carcinoma will develop in a patient with such a lesion ranges from l-5% (1,6,7). The patients who are most likely to develop cancer are those with microscopically proven atypical hyperplasia at initial examination. Women with lichen sclerosus combined with squamous cell hyperplasia are at somewhat increased risk for the development of atypia. In the absence of atypia, only a small risk is posed for the subsequent development of carcinoma. Any chronic irritative process of the vulva, however, adds to the risk of carcinoma. These patients must be closely followed and examined at regular intervals. Biopsies of the vulva should be performed on new lesions that develop or from areas of epithelial change that were not present at the last examination.

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Symptoms Pruritus is the principal symptom of patients with vulvardystrophies and is probably caused by degeneration and inflammation of terminal nerve fibers. Hyperplastic lesions appear to cause the most intense itching, whereas itching is often relatively mild in patients witli lichen sclerosus. Bruritus provokes scratching, which frequently produces excoriations and leads to further thickening of the skin and mucosa. Occasionally, patients complain of soreness and pain. Dyspareunia, especially in the presence of lichen sclerosus, is often reported. Shrinkage of the introitus sometimes makes intercourse impossible. Some patients may be free of symptoms, especially in the presence of lichen sclerosus.

Treatment Before treatment is instituted, biopsies should be performed on several areas of the vulva, especially from sites of fissuring, ulceration, induration, orthick plaques. Any possibly aggravating factors, such as trichomoniasis, candidiasis, allergy, diabetes, and fungal infections elsewhere in the body, should be taken into consideration; if any are found, the patient should be treated appropriately. Hygienic measures for keeping the vulva clean and dry should be recommended. Emotional factors should be investigated, since in some women stress results in vulvar pruritus, which promotes scratching and leads to further secondary skin changes. After the diagnosis and malignant potential of the lesions have been determined and all possible contributing factors eliminated, local measures for control of symptoms, primarily pruritus, can be instituted. If an eczematous type of vulvitis is present as the result of infected excoriations or ill-chosen medications, wet dressings with agents such as aluminum acetate (Burrow’s) solution applied frequently (three to four times daily for 30-60 minutes) are beneficial. Lotions and creams containing corticosteroids produce a rapid response and are more convenient to apply than wet dressings. Lesions demonstrating squamous cell hyperplasia are best treated by the local application of corticosteroids. The use of 0.025% or 0.01% fluocinolone acetonide, 0.01% triamcinolone acetonide, orsimilarpreparations two to three times daily will usually relieve

pruritus. A 7:3 combination of beta-methasone valerate, 0. l%, and crotamiton (Eurax), a potent antipruritic, is particularly effective when applied twice a day for 4 weeks. Fluorinated steroid substances should not be used for a prolonged period of time, since they may result in atrophy of the treated tissues. Therefore, when the pruritus is under control, these steroids should be replaced by a medication containing hydrocortisone. Hyperplastic lesions may significantly improve or disappear entirely once the pruritus is controlled. Topical testosterone offers the best results in the treatment of lichen sclerosus, improving both gross and histopathologic changes. Testosterone propionate, 2%, in petrolatum is easily prepared by a pharmacist. The ointment should be gently massaged into the tissues. Initially, the medication should be applied two or three times daily for at least 3-6 months or until pruritus is relieved. Thereafter, the frequency of application is gradually reduced until a maintenance level of once or twice weekly is reached. In the presence of severe pruritus, a mixture of 1% or 2.5% hydrocortisone in a petrolatum base and testosterone can be used. The use of testosterone has been studied in the treatment of lichen sclerosus and “mixed dystrophy”; of 184 women treated, 172 showed improvement after testosterone therapy (14). In patients who show no , response to the topical application of testosterone ointment or who experience adverse side effects from this , treatment, the topical application of progesterone ointment, mixed as a l-2% preparation in petrolatum, may be of benefit. Complex 15 has also been shown to be effective as a base for the preparation of a testosterone or progesterone mixture. Occasionally, vulvar pruritus is so persistent that it cannot be relieved by topical measures. In such cases, the intradermal injection of triamcinolone (10 mg/ml diluted to 2: 1 in saline) may be utilized; 0.1 ml of the suspension is injected at 1-cm intervals over the entire affected area, and the tissue is then gently massaged. If this treatment does not afford lasting relief of the pruritus, subcutaneous injection of absolute alcohol may relieve the symptoms. Aliquots of 0.1 ml of the alcohol are injected subcutaneously at l-cm intervals after the vulva has been carefully mapped out, and the vulvar area is thoroughly massaged to disperse the alcohol evenly. Alcohol injection can often be performed as a “day care” procedure, but it is preferable to keep the patient in the hospital overnight, since vulvar

ACOG

burning is sometimes intense and urinary retention occasionally occurs. Although this treatment produces relief of pruritus, it is of absolutely no value to the patient experiencing vulvar burning. The treatment of lichen sclerosus in children is directed primarily to the relief of pruritus. Intermittent topical corticosteroids should be used to avoid the side effects of testosterone. Alternatively, a mixture of progesterone, 100 mg, in oil per ounce of aquaphore may be effective. Although lichen sclerosus in children has been said to disappear spontaneously during or after adolescence, this is not always the case. Most children with this disease continue to demonstrate changes consistent with lichen sclerosus into adulthood.

The primary symptom of the vulvar dystrophies (nonneoplastic epithelial disorders of the vulvar skin and mucosa) is vulvar pruritus. The development of malignancy is relatively uncommon ( l-5%) over a prolonged period. Medical therapy is effective in alleviating symptoms in most patients.

REFERENCES Jeffcoate TNA. Chronic vulva dystrophies. Am J Obstet Gynecol 1%6;95( 1):61-74 Jeffcoate TNA. The dermatology of the vulva. J Obstet Gynaecol Br Comm 1962;69(5):888-890 Woodruff JD, Borkowf HI, Holzman GB, Arnold EA, Knaack J. Metabolic activity in normal and abnormal vulvar epithelia. Am J Obstet Gynecol 1965;91(6): 809-819 Friedrich EG, Julian CG, Woodruff JD. A&dine orange

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fluorescence in vulvar dysplasia. Am J Obstet Gynecol 1964;90(8):1281-1287 5. de Oliveira JM, Saleiro V. Involucrin expression in

vulvar lesions. J Reprod Med 1986;31(9):828-830 6. Hart WR, Norris HJ, Helwig EB. Relation of lichen sclerosus et atrophicus of the vulva to the development of carcinoma. Obstet Gynecol 1975;45(4):369-377 7. Kaufman RH, Gardner HL, Brown D Jr, Beyth Y. Vulvar dystrophies: an evaluation. Am J Obstet Gynecol 1974; 120(3):363-367 8. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus, and the effect of topical testosterone. N Engl J Med 1984;310(8):488-491 9. Meyrick Thomas RH, Ridley CM, Black MM. The association of lichen sclerosus et atrophicus in autoimmune-related diseases in males. Br J Dermatol 1983; 109(6):661-664 10. Harrington CI, Dunsmore IR. An investigation into the incidence of auto-immune disorders in patients with lichen sclerosus and atrophicus. Br J Dermatol 1981; 104(5):563-566 11. Meyrick Thomas RH, Holmes RC, Rowland PayneCME, Ridley CM, Sherwood F, Black MM. The incidence of development of autoimmune diseases in women after the diagnosis of lichen sclerosus et atrophicus. Br J Dermato1 1982;107(Suppl22):29 12. Sideri M, Rognoni M, Rizzolo L, Micheletti L, Barber0 M, Origoni M, et al. Antigens of the HLA system in women with vulvar lichen sclerosus: association with HLA-B21. J Reprod Med 1988;33(6):551-554 13. Douglas CP, Barnes CFJ. Proteolytic enzyme activity measured on extracellular matrix in vulvar dystrophies. J Obstet Gynecol 1986;6(3):193-195 14. Friedrich EG Jr. Vulvar dystrophy. Clin Obstet Gynecol 1985;28(1):178-187