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Non-infectious inflammatory genital lesions
Clinics in Dermatology (2014) 32, 307–314
Non-infectious inflammatory genital lesions Lucio Andreassi, MD a,⁎, Roberta Bilenchi, MD b a
Professor Emeritus, University of Siena, Italy Department of Dermatology, University of Siena, Italy
b
Abstract The genitalia may be the site of non-infectious inflammatory lesions that are generally manifested as balanoposthitis and vulvovaginitis. In men, these forms constitute 50% of all balanoposthitis forms, and in women, vulvovaginitis frequency is even higher. They consist of genital locations of general skin diseases, such as psoriasis, lichen planus, lichen sclerosus, and other clinical entities with their own physiognomy, such as Zoon’s balanitis-vulvitis. Diagnosis of genital noninfectious inflammatory lesions is usually made on clinical criteria. A biopsy is only necessary for the identification of clinical conditions that may simulate inflammatory form but are actually premalignant processes. © 2014 Elsevier Inc. All rights reserved.
Introduction In current clinical practice, there is a tendency to attribute a sexually transmitted origin to any pathologic condition involving the genitalia, especially in young people. The external genitalia are, however, also subject to inflammatory diseases completely unrelated to sexual transmission, as in the case of general skin diseases, such as psoriasis and lichen planus. Irrespective of the coexistence of systemic skin disorders, the genitals may be the site of non-infectious inflammatory processes having their own clinical physiognomy. It is also worth recalling that certain drugs can have side effects with a strong predilection for the genital region. Finally, it should not be forgotten that certain genital lesions, apparently of an inflammatory nature, are actually premalignant lesions that can progress to carcinoma, a severe condition with devastating psychologic repercussions. It is difficult to assess the frequency of non-infectious inflammatory lesions of the genitals. In men, they account for almost 50% of all cases of balanoposthitis with a percentage incidence of different forms as reported in a recent paper ⁎ Corresponding author. E-mail address: [email protected] (L. Andreassi). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.08.015
where irritations and allergies were in first position followed by lichen sclerosus and lichen planus.1 In women, the frequency of non-infectious genital lesions is even higher with irritative and allergic forms in first position.2 Non-infectious balanoposthitis and vulvovaginitis are manifested in ways that usually enable an exact diagnosis even if determining them requires accuracy and a certain experience. Because they are a possible source of diagnostic error that may have severe consequences for patients, we highlight the main clinical and other characteristics of non-infectious genital pathologies. We have provided a list (Table 1) of common non-infectious genital lesions, which includes the genital location of certain systemic skin diseases.
Genital involvement of systemic skin diseases Various systemic skin diseases may have genital locations. They are frequent in the case of vitiligo and bullous skin diseases, such as pemphigus and pemphigoid. Because they manifest themselves in the genital region with lesions that completely resemble those found in other sites, they are of no interest in a contribution dedicated to clinical
308 Table 1 The most common non-infectious forms of balanoposthitis and vulvovaginitis Genital involvement of systemic diseases Psoriasis Lichen planus Lichen sclerosus Erythema multiforme Irritative and allergic balanoposthitis and vulvitis Fixed drug eruption Zoon’s (plasmacytic) balanitis/vulvitis Erythroplasia of Queyrat/Bowen disease/bowenoid papulosis Nonspecific balanoposthitis and vulvitis
characteristics in relation to specific genital location. On the contrary, other skin diseases, such as psoriasis, lichen planus, lichen sclerosus, and erythema multiforme, may express themselves with genital lesions having their own physiognomy, which is important for diagnosis. Genital involvement is particularly frequent in psoriasis and lichen planus, which in some cases may involve this site as the first and only location with clinical pictures not always easy to interpret.3–5 Genital involvement is also relatively frequent in the case of atopic dermatitis, a condition that notoriously predisposes to irritation by aggressive stimuli and occasionally to sensitization phenomena. Genital lesions encountered in patients with atopic dermatitis are, therefore, discussed in the section on irritative and allergic forms.
Psoriasis The genitalia are involved in 30% to 40% of psoriasis patients with a slight prevalence in men.6 Genital involvement is associated with considerable psychologic suffering, especially in women. A recent study of a significant number of patients indicated that genital psoriasis has a negative effect on quality of life and especially on sexual relationships of affected subjects.7 The resulting psychologic complex makes psoriasis patients reticent to report genital involvement. Psoriatic lesions in the genital area present with different features in relation to the anatomical characteristics of the epithelium. In men, the skin of the penis has similar characteristics to that of the lower aspect of the abdominal wall. Proceeding from the external preputial lamina towards the glans penis and urethral meatus, the epidermis gradually acquires a mucosal appearance with intermediate characters on the glans, consisting of keratinized multilayered epithelium without hair and typical sebaceous glands. Likewise, in women, proceeding from the external vulva towards the vagina, the epithelium gradually acquires mucosal characteristics with an intermediate transition zone on the internal vulva. In men, the lesions have normal psoriatic appearance on more external areas, whereas in the balano-preputial area,
L. Andreassi, R. Bilenchi they tend to be less scaly, to weep in uncircumcised subjects, and to maintain a scaly appearance in circumcised subjects.8 Lesions may appear on the glans and prepuce as small elements or large patches. In some cases, location on the glans may be the first and only psoriatic lesion. In these patients, family medical history is fundamental, as is the identification of any other minimal lesions, such as lesions of the nail lamina (Figure 1). In women, as well, the clinical appearance of lesions depends on anatomical differences in the epithelium covering the external vulval region, including the labia major and the internal vulval regions. The most frequent site is the pubic region, where typical scaling, erythematous macules, or plaques are denser than in intermediate areas and may coalesce into larger lesions on the labia major.9 On the internal lamina of the labia major and labia minor and on the clitoris, the lesions are usually erythematous with few or no scales and sometimes with exudates.10 Exclusive involvement of the vulva may complicate the diagnosis, and psoriasis should be considered in all patients with chronic erythematous vulvitis without vaginitis.11 Penial and vulval psoriatic lesions are rarely pustular.
Lichen planus Lichen planus (LP) has an estimated frequency of about 1% in the general population and may involve different mucocutaneous areas of the human body.12 The genital mucosa is often affected in men and women, and simultaneous involvement of the oral mucosa is frequently observed. In a study of women with oral LP, more than 75% also had genital involvement, and half of these cases were asymptomatic.13 Simultaneous gingival and penile involvement of lichen planus is also relatively frequent in men.14 This finding suggests that all LP patients, especially those with oral lesions, should also undergo systematic genital examination.15
Fig. 1 Psoriatic balanitis as first and only skin lesion in a patient with multiple onychopathies.
Inflammatory genital lesions
309 The diagnosis of genital lichen planus is easy for the classical forms, especially when associated with oral localizations. Biopsy may be necessary for erosive vulvar forms and the specimen should be taken from the edge of eroded areas. The specimen reveals markers typical of LP.25
Lichen sclerosus
Fig. 2 Genital lichen planus with annular and erosive lesions of glans and prepuce.
The most common clinical expression of genital LP is leukokeratotic lesions, consisting of flat white papules that tend to join up into compact patches or networks. Other possible genital lesions are annular, of variable size, and sometimes confluent to form polycyclic figures (Figure 2). Genital LP often has a dominant erosive component, which is much more frequent in women and varies in intensity and area.16 Erosive LP in men mainly affects the glans, manifesting as bright red lesions that must be differentiated from Zoon’s balanitis and, in cases of sudden onset, also must be differentiated from fixed drug eruption.17 Erosive vulvar LP, in its early stages, is a frequent cause of vulvar pain. When fully developed, it mainly affects the labia minor and the vaginal introitus, the whole circumference of which may be bright red with areas of bleeding. Urinating causes pain and burning, and sexual intercourse is difficult.18,19 The labia minor and clitoris may regress and almost disappear. Sometimes, erosive LP lesions may affect the vagina wall, causing chronic inflammation, ulceration, and bleeding.20 Erosive vulvar LP may be complicated by squamous cell carcinoma. This may be recognized by clinical examination, which should be repeated at regular intervals in subjects at risk and combined with a histologic examination if necessary. Patients with mucosal, including genital, lichen planus may be carriers of hepatitis virus HBV and HCV. The incidence varies and is particularly significant in geographical areas where there is a high frequency of hepatitis viral infections.21,22 On this basis, it is advisable to test all patients with genital LP, especially those with erosive lesions, for markers of viral hepatitis. The role of viral hepatitis infection in the pathogenesis of LP is unclear, but it may be significant that cases of lichen have been observed, mainly in children, after vaccination for HBV.23,24
Lichen sclerosus (LS) has a clinical picture quite different from LP despite the possibility of some common aspects.26 Genital LS is seven times more common in women than men. It also occurs in childhood, especially in girls, but a proportion of cases of phimosis in boys may actually be cases of unidentified LS.27 In women, genital LS generally occurs with a series of subjective symptoms, such as itching, dyspareunia, and dysuria, that precede the manifestations of LS. In men, the appearance of lesions may likewise be preceded by subjective discomfort, but onset is more often characterized by evident lesions and, in rare cases, by sudden phimosis of a normally retractable prepuce or even by urinary obstruction. In the early stages, clinical manifestations are flat whitish papules, sometimes disposed in a network, consisting of a weave of linear reliefs separated by spared areas. In men, these lesions are located on the prepuce, in the balanic sulcus, and on the glans. In women, they are located on the inner surface of the labia major and minor. In this phase, the clinical features do not always enable a distinction between LS and LP.28 Later, the papular or reticular elements tend to join up and form leukokeratotic plaques of different shapes and sizes (Figure 3). In men, the plaques may be situated on the glans or on the prepuce, which can be interested in part or in all the circumference. In the latter case, the prepuce becomes rigid, causing slight to severe phimosis. In women, the sclerotic
Fig. 3 Lichen sclerosus of the penis, characterized by reticular pattern of papules confluent to form sclerotic plaques.
310
L. Andreassi, R. Bilenchi and constipation appear in a subsequent phase, due to vulvar sclerosis and in some cases perianal involvement.31 These subjective symptoms lead to scratching and, in some cases, bleeding, suggesting the possibility of sexual abuse, a diagnosis that needs to be carefully evaluated. A correct diagnosis comes from careful objective examination revealing the presence of vulvar and often also perianal sclerosis. The labia minor and perianal area are the structures most frequently involved (Figure 5).32
Erythema multiforme Fig. 4 Lichen sclerosus involving foreskin and glans with marked adherence on coronal sulcus.
plaques are mainly observed on the labia minor and vaginal introitus, the whole circumference of which may be involved, including the perianal region. The epidermis of the sclerotic areas may detach, giving rise to serum blisters that may evolve into areas devoid of epithelium. In both sexes, synechiae may develop. In women, the labia minor adhere to the labia major, whereas in men, the prepuce adheres to a greater or lesser degree to the glans (Figure 4). The vulva may progressively restrict the vaginal opening causing stenosis, in the past known as kraurosis vulvae. In men, the sclerotic prepuce may degenerate into complete phimosis, often associated with restriction of the urethral meatus, giving rise to balanitis xerotica obliterans. In this phase, and sometimes before, the development of squamous cell carcinoma is most common in both sexes.29 Infantile LS mainly affects prepuberal girls and generally manifests with pruritus, occasionally with pain.30 Dysuria
Erythema multiforme (EM) with genital involvement is relatively frequent and is most often encountered in the forms known as EM major, frequently induced by drugs, with aspects recalling Stevens-Johnson syndrome. The genital mucosa is seldom the only site involved; more often, there is simultaneous involvement of the mouth and lips, nasal choanae, conjunctiva, and anal region.33 Balanoposthitis due to EM is characterized by bullous lesions containing serum or blood, that may also involve the terminal part of the urethra, causing intense dysuria requiring catheterization for pain relief. Vulvovaginitis due to Stevens-Johnson syndrome may also have severe complications, consisting of the formation of synechiae of the labia minor and vaginal wall, requiring surgical treatment.34 Balanoposthitis and vulvitis due to EM must be differentiated from genital lesions due to fixed drug eruption. The finding of similar lesions near other orifices, especially the mouth, and the possible presence of classical “target” lesions in other sites usually makes it possible to confirm the diagnosis of EM. In cases suspected to be iatrogenic, it is appropriate to proceed as described below for genital location of fixed erythema.
Irritative and/or allergic balanoposthitis and vulvitis
Fig. 5 Lichen sclerosus in child with vulvar and perianal involvement.
Irritative reactions of the genital semimucosa are the most frequent forms of inflammatory non-infectious vulvitis and balanoposthitis. They are sometimes without any clear clinical picture, consisting of some degree of erythema in patches with scarcely defined borders observed relatively frequently in atopic patients.4 In men, they occur on the glans, prepuce, or both (Figure 6) with a higher incidence in uncircumcised individuals although possible also in circumcised men. In the latter, the erythematous component is often associated with fine scaling. A medical history of atopy and sudden fluctuating episodes in subjects practising obsessive genital hygiene are elements suggesting a diagnosis of irritative balanoposthitis.35 Other conditions of pathogenic importance include
Inflammatory genital lesions
311
Fig. 7 Fig. 6
Drug induced balanoposthitis.
Irritative balanoposthitis in subject with atopic dermatitis.
sexual practices involving intense friction, such as prolonged and repeated intercourse, homosexual intercourse, and masturbation.36 In women, irritative genital reactions affect both labia and especially the vaginal entrance and are a frequent cause of dyspareunia. They are encountered in all age groups and represent the majority of reactive vulvar disorders, also considering the high sensitivity of the vulvar region to irritation.37 Irritative vulvitis may also include some forms of vulvar vestibulitis syndrome, a notoriously chronic, heterogeneous, multifactorial disease characterized by pain on contact with the vaginal entrance and dyspareunia, fragile vestibular tissue (confirmed by contact) and objective evidence of different grades of vestibular erythema.38,39 Vulvar vestibulitis is a subset of vulvodynia that even afflicts many young women and may require surgical treatment for forms resistant to conservative therapies.40 In some cases of irritative balanoposthitis and vulvitis, sensitivity to specific allergens may develop with clinical manifestations that can be interpreted as the result of a biphasic irritative-allergic process in which the irritative stimulus is the major pathogenic component. Balanoposthitis induced by exclusively allergic mechanisms is reported to be rare. Among the most common allergens are rubber and its constituents, spermicides, and lubricants, agents that can be identified by contact testing.41 Allergic vulvitis is relatively frequent and often develops as sensitization to topical agents applied to treat genital manifestations of systemic skin diseases.42
Fixed erythema of the genitals usually presents with an acute erythematous, edematous reaction, accompanied by intense pruritus and/or needle-like pain, which often progresses to blister formation and subsequent erosion (Figure 7). The eruption that involves an area with clear borders is roundish and almost always single. In a few days it vanishes without trace, but erosive forms may ulcerate. In men, fixed erythema usually involves the glans and internal lamina of the prepuce but may also involve the external part of the prepuce and the skin of the penis, in which case it regresses, leaving evident pigmentation in the site of the previous inflammatory lesion. In women, the most frequent site is the vulvar region, which may be involved completely, including the labia major. The cause of fixed drug eruptions, historically linked to pyramidone and subsequently sulfonamides, certain antibiotics, and NSAIDs, has recently been extended to a surprising number of substances. Commonly incriminated drugs include antibacterial, antifungal, psychoactive, and analgesic drugs. An increasing list of many other substances, such as contrast media and plant extracts, have also been reported.44 Oral challenge tests are universally recognized as the most reliable method of identifying agents responsible for fixed drug eruption, but they cannot always be performed for riskrelated and medicolegal reasons. Other methods, such as patch tests and scratch tests, give disputable and unreliable results. In current practice, cases arising after taking many different drugs at the same time are not rare. In such cases, all suspected drugs should be suspended and reintroduced one at a time if needed for therapeutic purposes.
Fixed drug eruption Zoon’s balanitis-vulvitis Penis and vulva are preferential sites for fixed drug eruption. Genital involvement occurs in about 20% of cases and is preceded in order of frequency by the face, limbs, and trunk; however, considering the surface area of involved sites, the genitals are only exceeded as an elective site by the lips.43
First described in male genitalia,45 this chronic inflammatory disease was later recognized on the vulva.46 The recent identification of similar sets of histopathologic characteristics in the oral cavity and other superficial mucosa
312
L. Andreassi, R. Bilenchi vaginal discharge, and bleeding. In later stages, one or more erythematous lesions may appear and tend to join together. The site is usually the vulva, being less often found in the vagina, and identification may require histologic examination.51–54
Erythroplasia of Queyrat, Bowen disease, and Bowenoid papulosis
Fig. 8
Zoon’s balanitis.
suggests that all these forms can be grouped under the term idiopathic lymphoplasmacellular mucositis-dermatitis. 47 Zoon’s balanitis-vulvitis (ZBV) is a relatively frequent condition, especially in advanced age. Its origin is unclear, and its pathogenesis rests above all on histopathologic findings. In forms diagnosed early, there is slight thickening of the epithelium with parakeratosis and lichenoid infiltrate with lymphocytes and plasma cells. In more advanced cases, the epithelium atrophies with neutrophilic infiltrate and possible superficial erosion while dermal infiltrate becomes denser and consists prevalently of plasma cells. This sequence of histologic events suggests that ZBV may be promoted by non-specific stimulation of keratinized epithelium in a moist environment. This hypothesis is supported by findings initially identified as ZBV and later progressing to lesions with characters typical of other diseases, such as lichen planus and psoriasis.48 The hypothesis that ZBV may include a wide spectrum of inflammatory disorders is sustained by the finding of variable histopathologic characters observed on re-examination of cases previously classified as Zoon’s balanitis.49 Zoon’s balanitis spares circumcised men and begins as one or more roundish or polycyclic dark red patches with indistinct borders on the glans and/or internal preputial lamina. The lesions are initially without signs of infiltration but may develop slight dermal infiltration with erosion and weeping (Figure 8). The lesions, often diagnosed as an unspecified infection, are usually treated unsuccessfully with topical antibiotics or antimycotics. Clinical diagnosis is based on the following observations: the above morphological characters, age generally over 50 years, and prepuce completely covering the glans. Histologic confirmation is particularly appropriate to exclude carcinogenesis and specifically erythroplasia of Queyrat.50 In women, ZBV is considered relatively rare. Onset is usually associated with vulvar pain, pruritus, burning,
Erythroplasia of Queyrat (EQ), Bowen disease (BD), and Bowenoid papulosis (BP) have different clinical but histologically, similar patterns, being characterized by carcinoma in situ.55 In women, they are therefore currently termed vulval intraepithelial neoplasia.56 In men, the term penile intraepithelial neoplasia has been suggested but has not been accepted by everyone, so that conventional terminology is still used57; however, it is important to recall that these neoplasias in situ are often associated with the human papilloma virus (HPV), the presence of which is a further distinctive criterion also important for prognosis. Clinically, EQ is distinct from BP, whereas it is not as easy to differentiate EQ and BD. Patients with BP are younger than those with EQ and often have a history of HPV infection and sometimes concomitant immunosuppression. EQ patients may also have lichen planus or lichen sclerosus. These conditions almost always occur in uncircumcised subjects in the age range of 30 to 60 years, and they involve the glans and inner surface of the prepuce.58 Erythroplasia of Queyrat presents as a single infiltrated lesion or as multiple elements that progressively join to form a single plaque with polycyclic margins. The surface is smooth, velvety or slightly scaly, sometimes crusty or verrucous, and bright red in a color. The edges are always clearly demarcated and show infiltration, which can be appreciated by palpation. Evolution is characterized by slow progression; development of ulcerations or papulonodular lesions suggests transformation to invasive carcinoma.59,60 Cases initially resembling Zoon’s balanitis and later evolving into EQ have been described.61 Bowen’s disease, histologically identical to EQ, is relatively frequent on the skin but rare in the genital area where it has been described in circumcised men. The lesions usually consist of solitary, well-defined dark red scaly areas, often with crusts. Sometimes, the plaques may be highly pigmented, simulating melanoma. Bowen disease may also be preceded by a clinical and histologic picture typical of Zoon’s balanitis.62 Bowenoid papulosis presents with one or more papules resembling large flat warts. Their surface is usually smooth, dark red or greyish, and sometimes verrucoid. Lesions tend to join into large plaques and may be located in any genital area. In men, BP is found in the balano-preputial area on the external lamina of the prepuce down to the base of the penis and perianally. In women, BP may involve the whole vulva,
Inflammatory genital lesions including the labia major and the perianal region.63 Clinical diagnosis must be confirmed by histologic examination and HPV tests. HPV 16 is often found.
Non specific balanoposthitis In certain circumstances, the balanopreputial area may be the site of inflammation of non-infectious origin, induced by unspecified irritants. Such cases are labelled as non-specific balanoposthitis but respond to treatment with topical antiinflammatory drugs, such as pimecrolimus.64 The fact that these forms respond to pimecrolimus, a notoriously effective drug for atopic skin lesions, sheds doubt on their “non specificity” and suggests it may be worthwhile investigating irritants and sensitive skin as possible causes.
Conclusions The genitalia may be the site of non-infectious inflammatory processes, which are expressions of systemic skin diseases or have a clinical autonomy. In certain cases, the lesions may be the side effects of drugs, once restricted to a few antibiotics and NSAIDS but now attributable to an increasingly long list. Some genital lesions, which seem to be of an inflammatory nature, may actually be premalignant lesions that can evolve into aggressive tumors. In current clinical practice, the possibility of non-infectious genital lesions is often underestimated with a tendency to attribute a sexually transmitted origin to any pathological condition affecting the genitalia, especially in young people. It is, therefore, important to be aware of these cases. Their diagnosis is mostly based on typical clinical appearance and, in some cases, histopathologic examination, which should always be done on the basis of clinical indications.
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313 7. Meeuwis KA, de Hullu JA, van de Nieuwenhof HP, et al. Quality of life and sexual health in patients with genital psoriasis. Br J Dermatol. 2011;164:1247-1255. 8. Buechner SA. Common skin disorders of the penis. BJU Int. 2002;90: 498-506. 9. Farber EM, Nall L. Genital psoriasis. Cutis. 1992;50:263-266. 10. Meeuwis KA, de Hullu JA, Massuger LF, et al. Genital psoriasis: a systematic literature review on this hidden skin disease. Acta Derm Venereol. 2011;91:5-11. 11. Kapila S, Bradford J, Fischer G. Vulvar psoriasis in adults and children: a clinical audit of 194 cases and review of the literature. J Low Genit Tract Dis. 2012;16:364-371. 12. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25: 593-619. 13. Di Fede O, Belfiore P, Cabibi D, et al. Unexpectedly high frequency of genital involvement in women with clinical and histologic features of oral lichen planus. Acta Derm Venereol. 2006;86:433-438. 14. Petruzzi M, De Benedittis M, Pastore L, et al. Peno-gingival lichen planus. J Periodontol. 2005;76:2293-2298. 15. Rogers 3rd RS, Eisen D. Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival syndrome and the peno-gingival syndrome. Dermatol Clin. 2003;21:91-98. 16. Lewis FM, Shah M, Harrington CI. Vulval involvement in lichen planus: a study of 37 women. Br J Dermatol. 1996;135:89-91. 17. Cribier B, Ndiaye I, Grosshans E. Peno-gingival syndrome. A male equivalent of vulvo-vagino-gingival syndrome? Rev Stomatol Chir Maxillofac. 1993;94:148-151. 18. Kennedy CM, Galask RP. Erosive vulvar lichen planus: retrospective review of characteristics and outcomes in 113 patients seen in a vulvar specialty clinic. J Reprod Med. 2007;52:43-47. 19. Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:431-436. 20. Helgesen AL, Gjersvik P, Jebsen P, et al. Vaginal involvement in genital erosive lichen planus. Acta Obstet Gynecol Scand. 2010;89: 966-970. 21. Shengyuan L, Songpo Y, Wen W, et al. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145:1040-1047. 22. Daramola OO, George AO, Ogunbiyi AO, Otegbayo JA. Hepatitis B virus in Nigerians with lichen planus. West Afr J Med. 2004;23: 104-106. 23. Limas C, Limas CJ. Lichen planus in children: a possible complication of hepatitis B vaccines. Pediatr Dermatol. 2002;19:204-209. 24. Rebora A, Rongioletti F, Drago F. Parodi. Lichen planus as a side effect of HBV vaccination. Dermatology. 1999;198:1-2. 25. Neill SM, Lewis FM. Vulvovaginal lichen planus: a disease in need of a unified approach. Arch Dermatol. 2008;144:1502-1503. 26. Cooper SM, Ali I, Baldo M, Wojnarowska F. The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case–control study. Arch Dermatol. 2008;144:1432-1435. 27. Jasaitiene D, Valiukeviciene S, Vaitkiene D, et al. Lichen sclerosus et atrophicus in pediatric and adult male patients with congenital and acquired phimosis. Medicina (Kaunas). 2008;44:460-466. 28. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet. 1999;353: 1777-1783. 29. Gutiérrez-Pascual M, Vicente-Martín FJ, López-Estebaranz JL. Lichen sclerosus and squamous cell carcinoma. Actas Dermosifiliogr. 2012;103:21-28. 30. Poindexter G, Morrell DS. Anogenital pruritus: lichen sclerosus in children. Pediatr Ann. 2007;36:785-791. 31. Maronn ML, Esterly NB. Constipation as a feature of anogenital lichen sclerosus in children. Pediatrics. 2005;115:e230-e232. 32. Jensen LS, Bygum A. Childhood lichen sclerosus is a rare but important diagnosis. Dan Med J. 2012;59:A4424. 33. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and StevensJohnson syndrome: a review. Crit Care Med. 2011;39:521-532.
314 34. de Jesus LE, Dekermacher S, Manhães CR, et al. Acquired labial sinechiae and hydrocolpos secondary to Stevens-Johnson syndrome. Urology. 2012;80:919-921. 35. Birley HD, Walker MM, Luzzi GA, et al. Clinical features and management of recurrent balanitis; association with atopy and genital washing. Genitourin Med. 1993;69:400-403. 36. Sonnex C. Sexual hypersensitivity. Br J Hosp Med. 1988;39(40): 42,47-42,48. 37. Farage M, Maibach HI. The vulvar epithelium differs from the skin: implications for cutaneous testing to address topical vulvar exposures. Contact Dermatitis. 2004;51:201-209. 38. Marinoff SC, Turner ML. Vulvar vestibulitis syndrome: an overview. Am J Obstet Gynecol. 1991;65:1228-1233. 39. Groysman V. Vulvodynia: new concepts and review of the literature. Dermatol Clin. 2010;28:681-696. 40. Tommola P, Unkila-Kallio L, Paavonen J. Surgical treatment of vulvar vestibulitis: a review. Acta Obstet Gynecol Scand. 2010;89:1385-1395. 41. van Ulsen J, Stolz E, van Joost T, Geursen-Reitsma AM. Allergy to spermicidal lubricant in a contraceptive. Contact Dermatitis. 1987;17: 115-116. 42. Nardelli A, Degreef H, Goossens A. Contact allergic reactions of the vulva: a 14-year review. Dermatitis. 2004;15:131-136. 43. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838. 44. Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermatol. 2006;45:897-908. 45. Zoon JJ. Balanoposthite chronique circonscrite bénigne a plasmocytes. Dermatologica. 1952;105:1-7. 46. Garnier G. Vulvite érythémateuse circonscrite benigne a type éythroplasique. Bull Soc Fr Dermatol Syphilol. 1954;61:102-104. 47. Brix WK, Nassau SR, Patterson JW, et al. Idiopathic lymphoplasmacellular mucositis-dermatitis. J Cutan Pathol. 2010;37:426-431. 48. Weyers W, Ende Y, Schalla W, Diaz-Cascajo C. Balanitis of Zoon: a clinicopathologic study of 45 cases. Am J Dermatopathol. 2002;24: 459-467. 49. Alessi E, Coggi A, Gianotti R. Review of 120 biopsies performed on the balanopreputial sac. from zoon's balanitis to the concept of a wider spectrum of inflammatory non-cicatricial balanoposthitis. Dermatology. 2004;208:120-124.
L. Andreassi, R. Bilenchi 50. Pastar Z, Rados J, Lipozencić J, et al. Zoon plasma cell balanitis: an overview and role of histopathology. Acta Dermatovenerol Croat. 2004;12:268-273. 51. Toeima E, Sule M, Warren R, Igali L. Diagnosis and treatment of Zoon's vulvitis. J Obstet Gynaecol. 2011;31:473-475. 52. Fernández-Aceñero MJ, Córdova S. Zoon's vulvitis (vulvitis circumscripta plasmacellularis). Arch Gynecol Obstet. 2010;282:351-352. 53. Kim-Fine S, Torgerson RR, Wieland CN, Klingele CJ. Plasma cell mucositis of the vagina: a case report. Female Pelvic Med Reconstr Surg. 2012;18:252-254. 54. Virgili A, Levratti A, Marzola A, Corazza M. Retrospective histopathologic reevaluation of 18 cases of plasma cell vulvitis. J Reprod Med. 2005;50:3-7. 55. von Krogh G, Horenblas S. Diagnosis and clinical presentation of premalignant lesions of the penis. Scand J Urol Nephrol Suppl. 2000;205:201-214. 56. Scurry J, Wilkinson EJ. Review of terminology of precursors of vulvar squamous cell carcinoma. J Low Genit Tract Dis. 2006;10:161-169. 57. Henquet CJ. Anogenital malignancies and pre-malignancies. J Eur Acad Dermatol Venereol. 2011;25:885-895. 58. Porter WM, Francis N, Hawkins D, et al. Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol. 2002;147:1159-1165. 59. Graham JH, Helwig EB. Erythroplasia of Queyrat. A clinicopathologic and histochemical study. Cancer. 1973;32:1396-1414. 60. Kaye V, Zhang G, Dehner LP, Fraley EE. Carcinoma in situ of penis. Is distinction between erythroplasia of Queyrat and Bowen's disease relevant? Urology. 1990;36:479-482. 61. Starritt E, Lee S. Erythroplasia of Queyrat of the glans penis on a background of Zoon's plasma cell balanitis. Australas J Dermatol. 2008;49:103-105. 62. Davis-Daneshfar A, Trüeb RM. Bowen's disease of the glans penis (erythroplasia of Queyrat) in plasma cell balanitis. Cutis. 2000;65:395-398. 63. Obalek S, Jablonska S, Beaudenon S, et al. Bowenoid papulosis of the male and female genitalia: risk of cervical neoplasia. J Am Acad Dermatol. 1986;14:433-444. 64. Georgala S, Gregoriou S, Georgala C, et al. Pimecrolimus 1% cream in non-specific inflammatory recurrent balanitis. Dermatology. 2007;215: 209-212.
Non-infectious inflammatory genital lesions Lucio Andreassi, MD a,⁎, Roberta Bilenchi, MD b a
Professor Emeritus, University of Siena, Italy Department of Dermatology, University of Siena, Italy
b
Abstract The genitalia may be the site of non-infectious inflammatory lesions that are generally manifested as balanoposthitis and vulvovaginitis. In men, these forms constitute 50% of all balanoposthitis forms, and in women, vulvovaginitis frequency is even higher. They consist of genital locations of general skin diseases, such as psoriasis, lichen planus, lichen sclerosus, and other clinical entities with their own physiognomy, such as Zoon’s balanitis-vulvitis. Diagnosis of genital noninfectious inflammatory lesions is usually made on clinical criteria. A biopsy is only necessary for the identification of clinical conditions that may simulate inflammatory form but are actually premalignant processes. © 2014 Elsevier Inc. All rights reserved.
Introduction In current clinical practice, there is a tendency to attribute a sexually transmitted origin to any pathologic condition involving the genitalia, especially in young people. The external genitalia are, however, also subject to inflammatory diseases completely unrelated to sexual transmission, as in the case of general skin diseases, such as psoriasis and lichen planus. Irrespective of the coexistence of systemic skin disorders, the genitals may be the site of non-infectious inflammatory processes having their own clinical physiognomy. It is also worth recalling that certain drugs can have side effects with a strong predilection for the genital region. Finally, it should not be forgotten that certain genital lesions, apparently of an inflammatory nature, are actually premalignant lesions that can progress to carcinoma, a severe condition with devastating psychologic repercussions. It is difficult to assess the frequency of non-infectious inflammatory lesions of the genitals. In men, they account for almost 50% of all cases of balanoposthitis with a percentage incidence of different forms as reported in a recent paper ⁎ Corresponding author. E-mail address: [email protected] (L. Andreassi). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.08.015
where irritations and allergies were in first position followed by lichen sclerosus and lichen planus.1 In women, the frequency of non-infectious genital lesions is even higher with irritative and allergic forms in first position.2 Non-infectious balanoposthitis and vulvovaginitis are manifested in ways that usually enable an exact diagnosis even if determining them requires accuracy and a certain experience. Because they are a possible source of diagnostic error that may have severe consequences for patients, we highlight the main clinical and other characteristics of non-infectious genital pathologies. We have provided a list (Table 1) of common non-infectious genital lesions, which includes the genital location of certain systemic skin diseases.
Genital involvement of systemic skin diseases Various systemic skin diseases may have genital locations. They are frequent in the case of vitiligo and bullous skin diseases, such as pemphigus and pemphigoid. Because they manifest themselves in the genital region with lesions that completely resemble those found in other sites, they are of no interest in a contribution dedicated to clinical
308 Table 1 The most common non-infectious forms of balanoposthitis and vulvovaginitis Genital involvement of systemic diseases Psoriasis Lichen planus Lichen sclerosus Erythema multiforme Irritative and allergic balanoposthitis and vulvitis Fixed drug eruption Zoon’s (plasmacytic) balanitis/vulvitis Erythroplasia of Queyrat/Bowen disease/bowenoid papulosis Nonspecific balanoposthitis and vulvitis
characteristics in relation to specific genital location. On the contrary, other skin diseases, such as psoriasis, lichen planus, lichen sclerosus, and erythema multiforme, may express themselves with genital lesions having their own physiognomy, which is important for diagnosis. Genital involvement is particularly frequent in psoriasis and lichen planus, which in some cases may involve this site as the first and only location with clinical pictures not always easy to interpret.3–5 Genital involvement is also relatively frequent in the case of atopic dermatitis, a condition that notoriously predisposes to irritation by aggressive stimuli and occasionally to sensitization phenomena. Genital lesions encountered in patients with atopic dermatitis are, therefore, discussed in the section on irritative and allergic forms.
Psoriasis The genitalia are involved in 30% to 40% of psoriasis patients with a slight prevalence in men.6 Genital involvement is associated with considerable psychologic suffering, especially in women. A recent study of a significant number of patients indicated that genital psoriasis has a negative effect on quality of life and especially on sexual relationships of affected subjects.7 The resulting psychologic complex makes psoriasis patients reticent to report genital involvement. Psoriatic lesions in the genital area present with different features in relation to the anatomical characteristics of the epithelium. In men, the skin of the penis has similar characteristics to that of the lower aspect of the abdominal wall. Proceeding from the external preputial lamina towards the glans penis and urethral meatus, the epidermis gradually acquires a mucosal appearance with intermediate characters on the glans, consisting of keratinized multilayered epithelium without hair and typical sebaceous glands. Likewise, in women, proceeding from the external vulva towards the vagina, the epithelium gradually acquires mucosal characteristics with an intermediate transition zone on the internal vulva. In men, the lesions have normal psoriatic appearance on more external areas, whereas in the balano-preputial area,
L. Andreassi, R. Bilenchi they tend to be less scaly, to weep in uncircumcised subjects, and to maintain a scaly appearance in circumcised subjects.8 Lesions may appear on the glans and prepuce as small elements or large patches. In some cases, location on the glans may be the first and only psoriatic lesion. In these patients, family medical history is fundamental, as is the identification of any other minimal lesions, such as lesions of the nail lamina (Figure 1). In women, as well, the clinical appearance of lesions depends on anatomical differences in the epithelium covering the external vulval region, including the labia major and the internal vulval regions. The most frequent site is the pubic region, where typical scaling, erythematous macules, or plaques are denser than in intermediate areas and may coalesce into larger lesions on the labia major.9 On the internal lamina of the labia major and labia minor and on the clitoris, the lesions are usually erythematous with few or no scales and sometimes with exudates.10 Exclusive involvement of the vulva may complicate the diagnosis, and psoriasis should be considered in all patients with chronic erythematous vulvitis without vaginitis.11 Penial and vulval psoriatic lesions are rarely pustular.
Lichen planus Lichen planus (LP) has an estimated frequency of about 1% in the general population and may involve different mucocutaneous areas of the human body.12 The genital mucosa is often affected in men and women, and simultaneous involvement of the oral mucosa is frequently observed. In a study of women with oral LP, more than 75% also had genital involvement, and half of these cases were asymptomatic.13 Simultaneous gingival and penile involvement of lichen planus is also relatively frequent in men.14 This finding suggests that all LP patients, especially those with oral lesions, should also undergo systematic genital examination.15
Fig. 1 Psoriatic balanitis as first and only skin lesion in a patient with multiple onychopathies.
Inflammatory genital lesions
309 The diagnosis of genital lichen planus is easy for the classical forms, especially when associated with oral localizations. Biopsy may be necessary for erosive vulvar forms and the specimen should be taken from the edge of eroded areas. The specimen reveals markers typical of LP.25
Lichen sclerosus
Fig. 2 Genital lichen planus with annular and erosive lesions of glans and prepuce.
The most common clinical expression of genital LP is leukokeratotic lesions, consisting of flat white papules that tend to join up into compact patches or networks. Other possible genital lesions are annular, of variable size, and sometimes confluent to form polycyclic figures (Figure 2). Genital LP often has a dominant erosive component, which is much more frequent in women and varies in intensity and area.16 Erosive LP in men mainly affects the glans, manifesting as bright red lesions that must be differentiated from Zoon’s balanitis and, in cases of sudden onset, also must be differentiated from fixed drug eruption.17 Erosive vulvar LP, in its early stages, is a frequent cause of vulvar pain. When fully developed, it mainly affects the labia minor and the vaginal introitus, the whole circumference of which may be bright red with areas of bleeding. Urinating causes pain and burning, and sexual intercourse is difficult.18,19 The labia minor and clitoris may regress and almost disappear. Sometimes, erosive LP lesions may affect the vagina wall, causing chronic inflammation, ulceration, and bleeding.20 Erosive vulvar LP may be complicated by squamous cell carcinoma. This may be recognized by clinical examination, which should be repeated at regular intervals in subjects at risk and combined with a histologic examination if necessary. Patients with mucosal, including genital, lichen planus may be carriers of hepatitis virus HBV and HCV. The incidence varies and is particularly significant in geographical areas where there is a high frequency of hepatitis viral infections.21,22 On this basis, it is advisable to test all patients with genital LP, especially those with erosive lesions, for markers of viral hepatitis. The role of viral hepatitis infection in the pathogenesis of LP is unclear, but it may be significant that cases of lichen have been observed, mainly in children, after vaccination for HBV.23,24
Lichen sclerosus (LS) has a clinical picture quite different from LP despite the possibility of some common aspects.26 Genital LS is seven times more common in women than men. It also occurs in childhood, especially in girls, but a proportion of cases of phimosis in boys may actually be cases of unidentified LS.27 In women, genital LS generally occurs with a series of subjective symptoms, such as itching, dyspareunia, and dysuria, that precede the manifestations of LS. In men, the appearance of lesions may likewise be preceded by subjective discomfort, but onset is more often characterized by evident lesions and, in rare cases, by sudden phimosis of a normally retractable prepuce or even by urinary obstruction. In the early stages, clinical manifestations are flat whitish papules, sometimes disposed in a network, consisting of a weave of linear reliefs separated by spared areas. In men, these lesions are located on the prepuce, in the balanic sulcus, and on the glans. In women, they are located on the inner surface of the labia major and minor. In this phase, the clinical features do not always enable a distinction between LS and LP.28 Later, the papular or reticular elements tend to join up and form leukokeratotic plaques of different shapes and sizes (Figure 3). In men, the plaques may be situated on the glans or on the prepuce, which can be interested in part or in all the circumference. In the latter case, the prepuce becomes rigid, causing slight to severe phimosis. In women, the sclerotic
Fig. 3 Lichen sclerosus of the penis, characterized by reticular pattern of papules confluent to form sclerotic plaques.
310
L. Andreassi, R. Bilenchi and constipation appear in a subsequent phase, due to vulvar sclerosis and in some cases perianal involvement.31 These subjective symptoms lead to scratching and, in some cases, bleeding, suggesting the possibility of sexual abuse, a diagnosis that needs to be carefully evaluated. A correct diagnosis comes from careful objective examination revealing the presence of vulvar and often also perianal sclerosis. The labia minor and perianal area are the structures most frequently involved (Figure 5).32
Erythema multiforme Fig. 4 Lichen sclerosus involving foreskin and glans with marked adherence on coronal sulcus.
plaques are mainly observed on the labia minor and vaginal introitus, the whole circumference of which may be involved, including the perianal region. The epidermis of the sclerotic areas may detach, giving rise to serum blisters that may evolve into areas devoid of epithelium. In both sexes, synechiae may develop. In women, the labia minor adhere to the labia major, whereas in men, the prepuce adheres to a greater or lesser degree to the glans (Figure 4). The vulva may progressively restrict the vaginal opening causing stenosis, in the past known as kraurosis vulvae. In men, the sclerotic prepuce may degenerate into complete phimosis, often associated with restriction of the urethral meatus, giving rise to balanitis xerotica obliterans. In this phase, and sometimes before, the development of squamous cell carcinoma is most common in both sexes.29 Infantile LS mainly affects prepuberal girls and generally manifests with pruritus, occasionally with pain.30 Dysuria
Erythema multiforme (EM) with genital involvement is relatively frequent and is most often encountered in the forms known as EM major, frequently induced by drugs, with aspects recalling Stevens-Johnson syndrome. The genital mucosa is seldom the only site involved; more often, there is simultaneous involvement of the mouth and lips, nasal choanae, conjunctiva, and anal region.33 Balanoposthitis due to EM is characterized by bullous lesions containing serum or blood, that may also involve the terminal part of the urethra, causing intense dysuria requiring catheterization for pain relief. Vulvovaginitis due to Stevens-Johnson syndrome may also have severe complications, consisting of the formation of synechiae of the labia minor and vaginal wall, requiring surgical treatment.34 Balanoposthitis and vulvitis due to EM must be differentiated from genital lesions due to fixed drug eruption. The finding of similar lesions near other orifices, especially the mouth, and the possible presence of classical “target” lesions in other sites usually makes it possible to confirm the diagnosis of EM. In cases suspected to be iatrogenic, it is appropriate to proceed as described below for genital location of fixed erythema.
Irritative and/or allergic balanoposthitis and vulvitis
Fig. 5 Lichen sclerosus in child with vulvar and perianal involvement.
Irritative reactions of the genital semimucosa are the most frequent forms of inflammatory non-infectious vulvitis and balanoposthitis. They are sometimes without any clear clinical picture, consisting of some degree of erythema in patches with scarcely defined borders observed relatively frequently in atopic patients.4 In men, they occur on the glans, prepuce, or both (Figure 6) with a higher incidence in uncircumcised individuals although possible also in circumcised men. In the latter, the erythematous component is often associated with fine scaling. A medical history of atopy and sudden fluctuating episodes in subjects practising obsessive genital hygiene are elements suggesting a diagnosis of irritative balanoposthitis.35 Other conditions of pathogenic importance include
Inflammatory genital lesions
311
Fig. 7 Fig. 6
Drug induced balanoposthitis.
Irritative balanoposthitis in subject with atopic dermatitis.
sexual practices involving intense friction, such as prolonged and repeated intercourse, homosexual intercourse, and masturbation.36 In women, irritative genital reactions affect both labia and especially the vaginal entrance and are a frequent cause of dyspareunia. They are encountered in all age groups and represent the majority of reactive vulvar disorders, also considering the high sensitivity of the vulvar region to irritation.37 Irritative vulvitis may also include some forms of vulvar vestibulitis syndrome, a notoriously chronic, heterogeneous, multifactorial disease characterized by pain on contact with the vaginal entrance and dyspareunia, fragile vestibular tissue (confirmed by contact) and objective evidence of different grades of vestibular erythema.38,39 Vulvar vestibulitis is a subset of vulvodynia that even afflicts many young women and may require surgical treatment for forms resistant to conservative therapies.40 In some cases of irritative balanoposthitis and vulvitis, sensitivity to specific allergens may develop with clinical manifestations that can be interpreted as the result of a biphasic irritative-allergic process in which the irritative stimulus is the major pathogenic component. Balanoposthitis induced by exclusively allergic mechanisms is reported to be rare. Among the most common allergens are rubber and its constituents, spermicides, and lubricants, agents that can be identified by contact testing.41 Allergic vulvitis is relatively frequent and often develops as sensitization to topical agents applied to treat genital manifestations of systemic skin diseases.42
Fixed erythema of the genitals usually presents with an acute erythematous, edematous reaction, accompanied by intense pruritus and/or needle-like pain, which often progresses to blister formation and subsequent erosion (Figure 7). The eruption that involves an area with clear borders is roundish and almost always single. In a few days it vanishes without trace, but erosive forms may ulcerate. In men, fixed erythema usually involves the glans and internal lamina of the prepuce but may also involve the external part of the prepuce and the skin of the penis, in which case it regresses, leaving evident pigmentation in the site of the previous inflammatory lesion. In women, the most frequent site is the vulvar region, which may be involved completely, including the labia major. The cause of fixed drug eruptions, historically linked to pyramidone and subsequently sulfonamides, certain antibiotics, and NSAIDs, has recently been extended to a surprising number of substances. Commonly incriminated drugs include antibacterial, antifungal, psychoactive, and analgesic drugs. An increasing list of many other substances, such as contrast media and plant extracts, have also been reported.44 Oral challenge tests are universally recognized as the most reliable method of identifying agents responsible for fixed drug eruption, but they cannot always be performed for riskrelated and medicolegal reasons. Other methods, such as patch tests and scratch tests, give disputable and unreliable results. In current practice, cases arising after taking many different drugs at the same time are not rare. In such cases, all suspected drugs should be suspended and reintroduced one at a time if needed for therapeutic purposes.
Fixed drug eruption Zoon’s balanitis-vulvitis Penis and vulva are preferential sites for fixed drug eruption. Genital involvement occurs in about 20% of cases and is preceded in order of frequency by the face, limbs, and trunk; however, considering the surface area of involved sites, the genitals are only exceeded as an elective site by the lips.43
First described in male genitalia,45 this chronic inflammatory disease was later recognized on the vulva.46 The recent identification of similar sets of histopathologic characteristics in the oral cavity and other superficial mucosa
312
L. Andreassi, R. Bilenchi vaginal discharge, and bleeding. In later stages, one or more erythematous lesions may appear and tend to join together. The site is usually the vulva, being less often found in the vagina, and identification may require histologic examination.51–54
Erythroplasia of Queyrat, Bowen disease, and Bowenoid papulosis
Fig. 8
Zoon’s balanitis.
suggests that all these forms can be grouped under the term idiopathic lymphoplasmacellular mucositis-dermatitis. 47 Zoon’s balanitis-vulvitis (ZBV) is a relatively frequent condition, especially in advanced age. Its origin is unclear, and its pathogenesis rests above all on histopathologic findings. In forms diagnosed early, there is slight thickening of the epithelium with parakeratosis and lichenoid infiltrate with lymphocytes and plasma cells. In more advanced cases, the epithelium atrophies with neutrophilic infiltrate and possible superficial erosion while dermal infiltrate becomes denser and consists prevalently of plasma cells. This sequence of histologic events suggests that ZBV may be promoted by non-specific stimulation of keratinized epithelium in a moist environment. This hypothesis is supported by findings initially identified as ZBV and later progressing to lesions with characters typical of other diseases, such as lichen planus and psoriasis.48 The hypothesis that ZBV may include a wide spectrum of inflammatory disorders is sustained by the finding of variable histopathologic characters observed on re-examination of cases previously classified as Zoon’s balanitis.49 Zoon’s balanitis spares circumcised men and begins as one or more roundish or polycyclic dark red patches with indistinct borders on the glans and/or internal preputial lamina. The lesions are initially without signs of infiltration but may develop slight dermal infiltration with erosion and weeping (Figure 8). The lesions, often diagnosed as an unspecified infection, are usually treated unsuccessfully with topical antibiotics or antimycotics. Clinical diagnosis is based on the following observations: the above morphological characters, age generally over 50 years, and prepuce completely covering the glans. Histologic confirmation is particularly appropriate to exclude carcinogenesis and specifically erythroplasia of Queyrat.50 In women, ZBV is considered relatively rare. Onset is usually associated with vulvar pain, pruritus, burning,
Erythroplasia of Queyrat (EQ), Bowen disease (BD), and Bowenoid papulosis (BP) have different clinical but histologically, similar patterns, being characterized by carcinoma in situ.55 In women, they are therefore currently termed vulval intraepithelial neoplasia.56 In men, the term penile intraepithelial neoplasia has been suggested but has not been accepted by everyone, so that conventional terminology is still used57; however, it is important to recall that these neoplasias in situ are often associated with the human papilloma virus (HPV), the presence of which is a further distinctive criterion also important for prognosis. Clinically, EQ is distinct from BP, whereas it is not as easy to differentiate EQ and BD. Patients with BP are younger than those with EQ and often have a history of HPV infection and sometimes concomitant immunosuppression. EQ patients may also have lichen planus or lichen sclerosus. These conditions almost always occur in uncircumcised subjects in the age range of 30 to 60 years, and they involve the glans and inner surface of the prepuce.58 Erythroplasia of Queyrat presents as a single infiltrated lesion or as multiple elements that progressively join to form a single plaque with polycyclic margins. The surface is smooth, velvety or slightly scaly, sometimes crusty or verrucous, and bright red in a color. The edges are always clearly demarcated and show infiltration, which can be appreciated by palpation. Evolution is characterized by slow progression; development of ulcerations or papulonodular lesions suggests transformation to invasive carcinoma.59,60 Cases initially resembling Zoon’s balanitis and later evolving into EQ have been described.61 Bowen’s disease, histologically identical to EQ, is relatively frequent on the skin but rare in the genital area where it has been described in circumcised men. The lesions usually consist of solitary, well-defined dark red scaly areas, often with crusts. Sometimes, the plaques may be highly pigmented, simulating melanoma. Bowen disease may also be preceded by a clinical and histologic picture typical of Zoon’s balanitis.62 Bowenoid papulosis presents with one or more papules resembling large flat warts. Their surface is usually smooth, dark red or greyish, and sometimes verrucoid. Lesions tend to join into large plaques and may be located in any genital area. In men, BP is found in the balano-preputial area on the external lamina of the prepuce down to the base of the penis and perianally. In women, BP may involve the whole vulva,
Inflammatory genital lesions including the labia major and the perianal region.63 Clinical diagnosis must be confirmed by histologic examination and HPV tests. HPV 16 is often found.
Non specific balanoposthitis In certain circumstances, the balanopreputial area may be the site of inflammation of non-infectious origin, induced by unspecified irritants. Such cases are labelled as non-specific balanoposthitis but respond to treatment with topical antiinflammatory drugs, such as pimecrolimus.64 The fact that these forms respond to pimecrolimus, a notoriously effective drug for atopic skin lesions, sheds doubt on their “non specificity” and suggests it may be worthwhile investigating irritants and sensitive skin as possible causes.
Conclusions The genitalia may be the site of non-infectious inflammatory processes, which are expressions of systemic skin diseases or have a clinical autonomy. In certain cases, the lesions may be the side effects of drugs, once restricted to a few antibiotics and NSAIDS but now attributable to an increasingly long list. Some genital lesions, which seem to be of an inflammatory nature, may actually be premalignant lesions that can evolve into aggressive tumors. In current clinical practice, the possibility of non-infectious genital lesions is often underestimated with a tendency to attribute a sexually transmitted origin to any pathological condition affecting the genitalia, especially in young people. It is, therefore, important to be aware of these cases. Their diagnosis is mostly based on typical clinical appearance and, in some cases, histopathologic examination, which should always be done on the basis of clinical indications.
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