Nonspecific genital ulcers
Introduction
The presence of an erosion or ulcer over genitalia usually takes one's mind toward sexually transmitted infections (STIs); however, it is important to have a broader approach and consider non-STI causes, as well. Many of these, in fact, are diseases, which are more common than STIs. Wrongly labeling a patient as having a venereal disease can have great psychosocial implications, apart from the resultant wrong treatment.
An ulcer/erosion on genitalia can have infective and noninfective causes.1 Non-STI infective causes include: Epstein Barr virus, tuberculosis, leishmaniasis, HIV/AIDS related ulcers and amoebiasis. The list for noninfective causes is much longer and encompasses drug reactions, immunobullous disorders, aphthosis, Behcet's disease, inflammatory bowel disease, erosive forms of lichen planus and lichen sclerosis et atrophicus, premalignant and malignant conditions, pyoderma gangrenosum, and hidradenitis suppurativa.1
Section snippets
Reactive nonsexually related acute genital ulcers (RNSRAGU)/Lipschutz ulcer/ulcus vulvae acutum/acute genital ulcer2-6
RNSRAGU is a frequently encountered, often overlooked entity, affecting adolescent girls and young women. The development of acute, painful genital ulcer(s), generally preceded by nonspecific prodromal symptoms, is the usual presentation in a sexually inactive young girl/woman. The entity has grave sociocultural consequences, for it may invariably be diagnosed as a sexually transmitted disease.
Epidemiology
It is an uncommon entity for only a few case series2, 3, 4, 5, 6, 7 are thus far available; hence, its precise incidence is unknown.
Pathogenesis
It seems to be an outcome of a reactive process, triggered by distant infections. Accordingly, several reports describe the association of the reactive lesions with various infective pathogens. Benjamin Lipschütz (1878-1931) blamed these lesions on Bacillus grassus in 1912, which was later identified as Döderlein's bacillus.8 Epstein Barr virus (EBV), too, has been implicated.9, 10, 11 In addition to cytomegalovirus (CMV), Salmonella typhi, Salmonella paratyphi, the influenza virus, and
Clinical features
Lipschutz8 in 1913, described the presence of nonvenereal, acutely developing, genital ulcers in adolescent women, the ulcus vulvae acutum, the first of the three types, while the other two probably now would be classified as Behcet's disease or Crohn's disease.23
The usual presentation is that of a painful, usually single, genital ulcer developing acutely. It is frequently preceded by fever and nonspecific prodromal symptoms.6 Dysuria is common. It may be associated with oral aphthae. The ulcer
Diagnosis
The diagnosis of RNSRAGU is mainly clinical, which requires the exclusion of other common causes of genital ulceration. An acute genital ulcer developing in an otherwise healthy adolescent woman, without any sexual history and with a history of preceding fever or acute systemic illness, suggests the diagnosis.6
Examination of the oral mucosa, lymph nodes, and skin, plus a systemic evaluation, especially for hepatosplenomegaly, is essential.
Ruling out herpes progenitalis is prudent, this being
Treatment
The ulcer resolves spontaneously within 16-21 days, usually without any scarring.24 Pain relief and supportive measures are all that are required in most cases. Analgesics and topical anesthetics may be prescribed. In moderately severe disease, potent topical steroids, oral nonsteroidal anti-inflammatory drugs, and local anesthetics are required. In those with severe involvement (multiple lesions, necrotic ulcers), systemic steroids may be required.24 Systemic antibiotics may be given if needed
Prognosis
There may be a recurrence rate of 33%, as revealed in a series of 20 patients.7 A single episode of acute genital ulcer, without any evidence of a systemic disease, does not warrant further extensive evaluation; however, with recurrent oral and genital ulceration or significant extra-cutaneous involvement, an evaluation for Behcet's disease may be undertaken. When this has been ruled out, such patients may be deemed to have complex aphthosis.
Behcet's disease
This is a chronic relapsing systemic vasculitis of unknown origin. It is a multisystem disease and has a myriad of clinical features, posing a diagnostic challenge. The lack of an accepted and standardized laboratory diagnostic method makes clinical criteria the diagnostic cornerstone.26
Epidemiology
The disease is most prevalent along the “silk route,” with an incidence of 14-20 per 100,000, and within 100km on either side; 80-370 per 100,000 in Turkey, and about 0.1-7.5 per 100,000 in Europe and the United States.26, 27, 28, 29 It usually appears in the 3rd decade of life. It rarely develops before puberty or after the age of 50. The male to female ratio is now almost equal, although earlier reports had shown a higher prevalence in men.30 It runs a milder course in women as compared to
Pathogenesis
Vasculitis is the basic underlying pathology, with Behcet's being unique with a primary vasculitis and predominant venous involvement.31
A genetic predisposition, especially HLA-B51 association, has been incriminated for producing susceptibility.32, 33 The role of infectious agents, especially streptococcus, has been proposed.34 Antibodies to heat shock protein 60 (HSP60; a streptococcal protein) has been demonstrated. Increased serum levels of HSP60 occur but do not seem to correlate with the
Clinical features
Genital ulcer(s) form a part component of the diagnostic criteria for Behcet's disease.37 This is the second most common lesion seen in Behcet's disease, occurring in about 57% to 93% of patients.27 It may be the initial sign in 18% of patients.28 Their severity may range from small asymptomatic lesions to severely symptomatic ulcers, leading to secondary complications, especially in women.39, 40, 41, 42 The ulcers are oval and/or round, well demarcated with a grayish yellow necrotic base, and
Diagnosis
This is based on clinical criteria and relies heavily on mucocutaneous signs. When a diagnosis of Behcet's is suspected a detailed systemic evaluation must be undertaken to look for involvement elsewhere. Other systems commonly involved include: ocular, articular, neurological, gastrointestinal, urogenital, pulmonary, vascular, and cardiac.
Various clinical criteria have been proposed, for which the International Study Group criteria include47:
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recurrent oral ulceration
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minor aphthous
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major aphthous
Histopathology
It is characterized by vasculitis and thrombosis. Early mucocutaneous lesions show neutrophilic vascular reaction with endothelial swelling, red blood cell extravasation, and leukocytoclasis or a fully developed leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls.53, 54
Treatment
Topical treatment of genital ulcers of Behcet's disease includes corticosteroids and anaesthetics.26 Topical sucralfate may reduce the healing duration and pain.55, 56 Intralesional corticosteroids can be employed in recalcitrant ulcers.26
Severe mucocutaneous disease warrants systemic management, which predominantly involves the use of varying combinations of the following: corticosteroids, colchicines, dapsone, interferon-alpha, thalidomide, azathioprine, cyclosporine A, methotrexate, and
Complex aphthosis
Complex aphthosis (CA), is the presence of almost constant, multiple (≥ 3) oral or oral and genital aphthae (Figures 1A and B) in the absence of systemic manifestations.62 The clinical appearance of oral and genital lesions is similar to that described in BD.39 This entity is probably a subset of recurrent aphthous stomatitis, defined as the recurrence of one or more painful oral ulcers at intervals ranging from a few days to months.39 It becomes crucial to distinguish this entity from Behcet's
Crohn's disease
Crohn's disease (CD) is a chronic granulomatous inflammatory bowel disorder that may involve any segment of the gastrointestinal tract. Mucocutaneous lesions are its most frequent extra intestinal manifestations, seen in 22% to 75% of patients.88, 89 Cutaneous manifestations, on the other hand, are in the form of granulomatous infiltrations, reactive dermatoses, and skin changes resulting from nutritional deficiencies.90 There are direct involvement of the contiguous sites such as perianal
Epidemiology
CD incidence ranges from 3.1 to 14.6 per 100,000 person-years in a review of large population-based patient cohorts' studies91 in North America. Its incidence of perianal involvement is as low as 3.8%92 and as high as 61% to 80%.93, 94, 95 This variation is partly related to different defining criteria. MCD in adults usually appears long after the initial diagnosis of CD in 70% of the patients, and it has rarely been reported as the initial symptom.96 MCD appears at the same time as CD in
Pathogenesis
The etiology of MCD is unknown. It is probable that antigens or immune complexes get deposited in the skin, creating microscopic perivascular granulomas in primary Crohn's disease of the gastrointestinal tract.88 Autoimmune cross-reactivity has also been proclaimed, where antibodies specific to antigens in the gastrointestinal tract may react with skin antigens of similar structure.97 The granulomatous inflammation may also be due to a type IV hypersensitivity reaction wherein T cells
Clinical features
Contiguous involvement of the perianal region can present as cavitating ulcers with or without lymphedema, polypoid skin-tag like lesions, moist plaques, fissures, fistulas, sinus tracts, anorectal strictures, and abscesses.99 The characteristic early lesions are small erythematous papules that may enlarge to become nodular and ulcerate exuding purulent discharge.96 MCD can present as genital ulcers in adults; however, more commonly, it presents as nodules and/or plaques with or without
Diagnosis
Presence of CD of the gastrointestinal tract simplifies the diagnosis; however, difficulty may arise in cases where gastrointestinal activity is absent or those having a suggestive sexual history. Histopathology is characterized by discrete, noncaseating, sarcoidal granulomas with numerous foreign body and Langhan's type multinucleated giant cells present more commonly in the superficial dermis, deep dermis and adipose tissue.96 Often, there is perivascular, the granulomatous perivasculitis or
Treatment
Evidence for treatment modalities of cutaneous CD is mainly anecdotal. Oral metronidazole is often effective. Other treatments include various chemotherapeutic agents, including oral steroids,105, 106, 107, 108, 109 topical steroids,109, 110 azathioprine,106, 107, 111 cyclosporine,112, 113 sulfasalazine,113, 114 and tetracyclines.115 Patients with perianal CD seem to be resistant to systemic steroids.116 Topical tacrolimus has been used successfully in the treatment of perineal CD.117, 118 Oral
Prognosis
Although spontaneous resolution of MCD has been described, complete resolution is uncommon and unpredictable.128 Surgical removal of the affected bowel does not necessarily improve MCD.129 Treatment is often unsatisfactory, as adequate evidence-based management is lacking. When a diagnosis of MCD is made, the likelihood of subsequent onset of CD is 2 months to 4 years in adults with a mean of 2.66; median, 2 years and 9 months to 14 years (mean, 4.6; median, 3.9 years) in children.96
Pyoderma gangrenosum
Pyoderma gangrenosum (PG) is a rare, chronic, often destructive, inflammatory skin disease130 the incidence of which is about 3 to10 patients per million population per year.130
Its pathogenesis is not well understood; however, neutrophil dysfunction does have a role. IgA gammopathies, impairing neutrophil chemotaxis in vitro, are not uncommon.131 Circulating immunoglobulins affecting neutrophil functions and monoclonal or polyclonal hyperglobulinemia is frequent; moreover, interleukin-8 (IL-8),
Clinical variants
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Ulcerative,
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Pustular,
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Bullous
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and Vegetative.
Genital lesions affecting the vulva, penis, and scrotum are known. An ulcerative variant is common. The ulcer typically has a raised inflammatory, dusky red/purplish border and a boggy necrotic base. The primary lesion starts as a deep-seated, painful nodule or as a superficial hemorrhagic pustule, either de novo or after minimal trauma. The actively advancing ulceration may expand more rapidly in one direction resulting in a serpiginous pattern.130 The
Treatment
Localized, mild disease may be managed with topical therapy alone, which includes topical corticosteroids, tacrolimus, and imiquimod. Severe disease warrants systemic management. The most promising results are obtained with systemic corticosteroids and cyclosporine.130 Other drugs that have shown beneficial results include dapsone, sulfasalazine, clofazamine, colchicines, minocycline, immunosupressives (azathioprine, methotrexate, cyclophosphamide), IVIG, and biological (especially infliximab).
Prognosis
PG is an unpredictable disease. It can have a rapid dramatic onset and course or may be a slowly developing and indolent process. When associated with ulcerative colitis, the disease activity of pyoderma gangrenosum may parallel that of the bowel disease: the control of the intestinal condition can resolve the skin problem and recurrences may occur at periods of exacerbation of IBD. Skin lesions may also have an evolution that is partially independent of the intestinal activity of IBD. The
Drug induced
Erythema multiforme (EM) is rarely associated with genital lesions, whereas oral lesions are nearly always present.152 The genitalia is more frequently affected in Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), often with erosions.152, 153 In a series154 of 40 patients with TEN, 28 had severe vulvo-vaginal involvement that resulted in permanent scarring in five of them.
Fixed drug eruptions (FDEs) are peculiar cutaneous eruptions characterized by solitary/multiple, round
Immunobullous disorders
Pemphigus vulgaris (PV) may cause genital erosions (Figure 3). In one series162 of 34 patients with PV, 21 had labial involvement, 3 had vaginal lesions, and 10 had labial and vaginal involvement. Although PV generally does not lead to scarring, vulvo-vaginal lesions may result in scarring.163 There is a confirmed case of PV limited only to the prepuce.164
Cicatricial pemphigoid (CP) may have an exclusive genital involvement in isolation. In addition to erosions, vaginal scarring/phimosis may be
Lichen planus
Erosive mucosal lichen planus (LP) is a well-established variant of LP characterized by the formation of ulcerative lesions predominantly involving the oral and genital mucosa.
In women, it involves the vaginal orifice and often the labia minora. In men, the disease may involve the glans and prepuce. The lesions are erythematous, partly erosive and desquamative, occasionally, surrounded by a pale border (Figure 4). It causes severe symptoms like burning, pain, pruritus, and dyspareunia.168
Lichen sclerosus et atrophicus
Erosions and ulcerations may develop over genital lichen sclerosus et atrophicus (LSA).181 Severe itching is a feature. Extension may occur into the perianal region in a “figure eight.” There may be dysuria, pain on defecation, and dyspareunia. Presence of cutaneous lesions and histopathology may suggest the diagnosis. Treatment is difficult and consists mainly of potent topical steroids and calcineurin inhibitors. There are various reports182, 183, 184 of systemic treatments, including
Amoebiasis
Cutaneous amoebiasis (CA) is an uncommon manifestation of Entamoeba histolytica even in endemic regions.185 The infection affects the skin when amoebae escape from the bowel to the contiguous skin or any discharge containing virulent trophozoites remains in prolonged/repeated contact with traumatized skin.186 The vulval/perineal region is highly vulnerable; but involvement of glans is rare and may occur from direct inoculation by anal /vaginal intercourse with a person suffering from amoebic
Candidosis
Candidal infection can lead to erosive lesions over the vulva and glans. It may be a STI, or there may be an underlying dermatological or medical cause, although the symptoms and signs of Candida may be more florid than the underlying predisposing cause. Medical causes include diabetes mellitus, high-dose oral contraceptive agents, pregnancy, iatrogenic immunosuppression, and systemic antibiotic treatment.152
Diagnosis is confirmed by direct microscopy and culture. Treatment of genital
Varicella-zoster virus
Sacral zoster can affect the vulva, penis, and scrotum. It may be accompanied by bowel and bladder dysfunction.210, 211
Other bacterial etiologies that may present with genital ulcerations/erosions include streptococcal cellulitis,212 Buruli ulcer due to Mycobacterium ulcerans,213 nonsyphilitic spirochaetal ulcerative balanoposthitis,214 genital ulceration associated with disseminated early yaws215 and bullous necrotic erysipelas of the penis due to Streptococcus pyogenes.216 Ecthyma gangrenosum
Chancroidal ulcer
Chancroidal ulcer223 is characterized by a single ulcer that has well-defined, soft, tender, nonindurated and weakening edges. It has a longer incubation period of 8 to 11 days. Absence of lymphadenopathy is a prominent feature. The male/female ratio being 27/1. Persons of low socioeconomic status in the sexually vulnerable age-group are predominantly affected. The prepuce, coronal sulcus, and glans penis are common sites, as is the labia minora. Due to the limited value of gram-stained smears
Men
About 35% cases of penile carcinoma present as a sore or ulcer.224 Associated clinical manifestations may include pain, discharge, bleeding, and foul odor. The ulcer gradually enlarges and infiltrates deeper in the tissue. Lymph nodes are affected in later stages. The disease may develop de novo or be preceded by certain at-risk conditions like LSA, erosive LP, chronic balanitis, leukoplakia and in-situ carcinomas, erythroplasia of Queyrat, Bowen's disease, and bowenoid papulosis.225 Biopsy of
Zoon's balanitis and vulvitis
In 1952, Zoon first described, under the nomenclature of balanitis chronica circumscripta plasmacellularis, a chronic inflammation of the glans penis or inner surface of the foreskin, clinically resembling the erythroplasia of Queyrat, and histologically characterized by an infiltrate of plasma cells.235 Garnier, in 1954, described the female equivalent of it, which is much less common.236
Zoon's balanitis (or plasma cell balanitis or balanitis circumscripta plasmacellularis) is a disorder
Factitial
Erosions/ulcerations of the genitalia may occur during sexual intercourse or may be self-induced. Lesions in dermatitis artefacta are typically geometrical, angulated, and curvilinear.152, 242 Sometimes, they are induced by needles, knives, or cigarette burns, and extraneous foreign material may be introduced into the skin (lipogranuloma and silicone granuloma).243, 244 Association with an atypical behavioral pattern or underlying personality disorder should be evaluated.242
Others
Ulceration of the penis and scrotum following application of tazarotene gel and imiquimod has been described.245, 246 Inadvertent subcutaneous injection of papaverine for the treatment of erectile impotence may result in a genital ulcer(s).247 Foscarnet is a recognized cause in HIV-infected patients.248, 249 Nicorandil250, 251 is another newly implicated cause.
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