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Introduction

The Lipschütz ulcer is a non-sexually transmitted condition. It has been considered as an


uncommon and probably underdiagnosed entity, although a recent study has reported that it may
represent around 30% of vulvar ulcerations.1 Despite the characteristic symptoms, the disease
is very rare and is usually misdiagnosed by specialists. In 1913, Lipschütz described an acute
clinical entity characterised by the sudden appearance of necrotic painful genital ulcerations, fever
and lymphadenopathy that occurred mostly in adolescent and virgin girls.1–3 It usually reaches
young virgin girls even before the beginning of their sexual life [2]. In the century since this report,
little progress has been made toward understanding these ulcers. Today, the term “Lipschutz ulcer”
refers to an ulceration of the vulva or lower vagina of nonvenereal origin and is also known as
“ulcus vulvae acutum” or “acute genital ulcer” (AGU) (2).The published literature is limited to
case reports and case series. The differential diagnosis of AGU includes lichen planus, lichen
sclerosus, pemphigus, pemphigoidandherpes simplex virus infection.
However, by definition, Lipschutz ulcers are vulvar ulcers that do not have an identifiable etiology,
based on clinical, histopathologic and direct cytotoxic microbiologic findings. Fear and shame
mayprevent patients fromseeking care,andproviders may fail to recognize this unique subset of
patients. Thus the natural history, etiology, and effective treatment and prevention measures are
still incompletely understood. AGU are painful and distressing to women and perplexing to the
providers who care for them. Because of the rarity of these lesions, women may be referred to
dermatologists, gynecologists, or rheumatologists, depending upon local resources and referral
patterns. It is important for the practicing dermatologist to be aware of this challenging AZQentity.
The aims of this article are to review the differential diagnosis and pathogenesis of AGU, and to
discuss treatment options for the dermatologist who cares for women and girls with vulvar ulcers.
In the context of this article, the term “women” applies to girls and women regardless of their age
or reported sexual activity.

Prevalensi
Hyperacute genital ulceration generally occurs in young women, predominantly virgins,1
although cases of ulceration occurring after defloration have also been reported.

Etiologi
Since the first description[1], the etiology of this condition has been very difficult to define and
have been discussed. The etiology is most often unknown, but it is most often a contemporary
episode of an infection. Lipschutz assumed that the disease was caused by autoinoculation with
Bacillus crassus (later named as Doderlein's lactobacillus), while others ascribed generically the
disease to poor hygiene of young women[3]. Primary EBV infection is most often reported, but
this is not systematic [3]. Viral pathogens may cause ulcers. The reported rate of EBV associated
with AGU seems to be around 30%.6 Other pathological agents have been found to be associated
with episodes of AGU, including CMV, paratyphoid fever, influenza A, Toxoplasma gondii and
Mycoplasma.1–4 7 8 Chanal et al5 have also reported a case of AGU associated with mumps. The
pathophysiological mechanism of ulcer in these cases is unknown. It has been suggested a direct
cytotoxic effect, a role of B lymphocytes EBV-infected or a reactive process typically triggered
by a distant infection.1 4
Episodic reports refer about hypothetic association of ulcus vulvae acutum with Paramixovirus in
a 21-year-old girl with bilateral parotitis[6], with Influenza A virus in a 13-year-old girl[7], with
Salmonella typhi and parathyphi A infection[8]. A case of Ulcus vulvae acutum with cold-
agglutinin-positive,
Mycoplasma-caused atypical pneumonia has been reported[9]. In a very recent series Mycoplasma
pneumoniae has been recognized in one out of 12 cases of acute genital ulcers in nonsexually
active young girls, while work-up failed to reveal a specific infectious or autoimmune etiology in
the remaining 11 cases[10]. Another recent review of 13 pubertal girls with nonsexually related
acute genital ulcer[11] revealed a heterogeneity of clinical and microbiological findings, but the
final diagnosis was Epstein-Barr virus primary infection in 4 patients (31%) and Behcet disease in
1 patient (8%). No other infectious agents were detected in this series.
A large series from Brazil reports 33 cases of Lipschutz ulcer [27] , about one third of 110 cases
of vulvar ulcer seen during 5 years in a Vulvar Clinic: a microbiological possible cause was
identified only in 9 (27.3%) patients: CMV (3 cases), Mycoplasma pneumoniae (3 cases), EBV (2
cases) and PVB19 (1 case). Horie and coll. [28] report three consecutive cases of young women
with Lipschutz ulcer associated with a recent Mycoplasma fermentans infection. Haidari and coll.
[29] report the first case of influenza B virus and adenovirus infections associated with the
presentation of Lipschutz ulcer. Finally, from Hungary, Kinyo and coll.[30] report two cases
without a detectable infective cause, while both patients had partial IgA deficiency, therefore the
Authors emphasize the possible role of local immunological mechanisms rather than several
infectious agents in the development of this little-known disease.
Clinical presentation
It affects mainly adolescents and young adults, but there are reported cases in children. The clinical
appearance starts with a sudden onset of fever, chills, and malaise without any precedent.
Three to 4 days later, painful ulcers appear on the internal surface (vestibulum) of the labia
minora, but they can affect the labia majora as well. The symptoms are accompanied by
dysuria. Based on macromorphologic findings, three main forms of the course of the disease
can be identified. The gangrenous form has a characteristic hyperacute onset, ulcers covered
with grayish-yellowish encrustation, and extreme pain. Crusts slough in several days with
scarring. This form is the most frequent. The chronic form (pseudoveneric Lipschütz ulcer,
Scherber’s pseudotuberculotic form) is a relapsing form with marked edema and circular or
partial undercut superficial ulcers.
It presents as a sudden onset of painful vulvar ulcers, usually wider than 1 cm and deep, with a red
border and a necrotic centre covered by grey exudate or grey-black eschar,2 sometimes preceded
by unspecific nongynaecological symptoms. Bilateral ‘Kissing lesions’ are characteristic. The
diagnosis is mainly clinical and made by exclusion after ruling out other causes of genital
ulcerations. Vulvar ulceration, whether single or multiple, is a painful and distressing condition
that be seen in a variety of contexts.Viral pathogens (such as herpes simplex virus [HSV] and
Epstein-Barr virus [EBV]) may cause ulcers by direct cytotoxic effect. Alternatively, ulcers may
be a nonspecific inflammatory response to systemic illness or infection. In these cases, histologic
examination shows nonspecific inflammation (2–4), and electron microscopic findings suggest
that microthrombi in epidermal blood vessels lead to ischemia, necrosis, and ulceration of the
dermis (3).

Classically, Lipschutz ulcers present as single or multiple, shallow ulcers with raised, sharply
demarcated borders (FIG. 1).Many have an overlying gray exudate (pseudomembrane) or adherent
gray-brown eschar (FIG. 2). Secondary erythema and edema may be impressive; cellulitis should
be considered. Typically, ulcers occur on the medial aspects of the labia minora, but they are also
found on the labia majora, perineum, and in the lower vagina. “Kissing” ulcers on apposing
surfaces are common (FIG. 1) (2,3). Most reports describe lesions greater than 1 cm in diameter,
but the size varies. Many patients present with fever, malaise and oral aphthae (2,3). Less
commonly, patients had skin nodules consistent with erythema nodosum, and fine reticular rash of
the torso was present in several reported cases (2,3). There is some variety in lesion appearance,
depending on when a woman presents for care. Occasionally, patients initially present with dark
red or black pseudovesicles (FIG. 3) that may then develop an eschar with underlying painful ulcer
(FIG. 4). As these resolve, a small area of granulomatous tissue (FIG. 5) may be seen before
healing is complete. Some patients present with multiple ulcers in a “herpetiform” distribution
(FIG. 6), whereas others present with one or more ulcers with eschar (FIG. 2). Although the single
most common cause of vulvar ulcers is sexual transmission of HSV, it is imperative that clinicians
be aware of the nonsexually transmitted diseases that can result in vulvar ulceration. As well as the
characteristic labial localization, involvement of the vagina and urethra are also reported. Aphthous
buccal mucosa occurring in parallel with polymorphic and nodose erythema can be regarded as an
extragenital form of the disease.8 The latter forms might probably be ascribed to Behçet’s syndrome and
primary herpes infection. The intimate and culturally sensitive nature of genital disorders may cause
significant distress to the patient, her family and provider. Therefore, it is important to maintain a
nonjudgmental and sensitive approach to the patient with vulvar ulcers.
The ulcers usually heal in 4 to 6 weeks. The miliar form involves purulent, fibrinous ulcers
with inflammatory edges of a pinhead size. The ulcers typically affect the margins of the labia
majora and minora, as well as the perineal region. The general symptoms are mild and
healing is fast.

Differential diagnosis
The differential diagnosis of AGU includes sexually and nonsexually transmitted infections, drug
reactions, autoimmune conditions, local manifestations of systemic illnesses, as well as
idiopathic aphthosis (Table 1). The disease should be differentiated from venereal (syphilis, ulcus
molle) and nonvenereal infections (herpes simplex, herpes zoster, miliar ulcerative tuberculosis).
Of the noninfectious diseases, Behçet’s syndrome, different aphthae, Reiter’s syndrome, anovaginal
fistula, and myeloproliferative diseases should be primarily considered.8,9 Evaluation of the whole skin
surface and the mucosa might help in the differential diagnosis.
Sexually transmitted infections such as HSV, syphilis, lymphogranuloma venereum, and
chancroid arewell-known causes of AGU(5). It is important to take a thorough sexual history,
including screening for abuse, recognizing that patients may be reluctant to share these intimate
details. In the United States, HSV is the most common of these sexually transmitted infections and
it is important to remember that nonsexual transmission of either type 1 or type 2 HSV can occur
(6–8). In a study of 53 adult Brazilian women with AGU, approximately
60% had HSV infection (9). In a prospective study of over thirty adolescents referred for acute
vulvar ulcers, all initially denied sexual contact. About 10% were documented as having HSV
infection suggesting that the initial history may not always be reliable (3). Most women who
present with AGU also report nonspecific systemic symptoms, such as fever and myalgia.
Although this presentation may suggest an infectious etiology, no viral, bacterial, or fungal
pathogen was identified for over 75% of patients in two case series (2,3).
EBV may be a direct or indirect cause of nonsexually transmitted ulcers. Sixteen published reports,
totaling 25 cases of vulvar ulcers, have been temporally associated with EBV infection in young,
nonsexually active women. In five cases, EBV was recovered from the ulcer by viral culture (10)
or polymerase chain reaction (PCR) (2,11,12).
Table 1. Differential diagnosis of acute vulvar
ulcers (in order of estimated prevalence)
Infection
Sexually
transmitted
Herpes simplex virus
Syphilis
Lymphogranuloma venereum
Chancroid
Human immunodeficiency virus
Nonsexually
transmitted
Herpes simplex virus
Epstein-Barr virus
Cytomegalovirus
Influenza A
Paratyphoid
Systemic illness Crohn’s disease (metastatic or
contiguous fistula)
Cyclic neutropenia
PFAPA syndrome (periodic fever,
aphthous stomatitis, pharyngitis,
adenitis)
MAGIC syndrome (mouth and
genital ulcers with inflamed
cartilage)
Iron, folate, vitamin B12 deficiency
Behçet’s disease
Hormone-related Autoimmune progesterone
dermatitis
Drug reaction Nonsteroidal anti-inflammatory
Drugs

In twenty cases, EBV infection was documented only by serologic testing (2–4,11–25). This
suggests that EBV can cause both direct cytotoxicity of vulvar epithelium as well as trigger an
immunologic response that manifests as vulvar ulcers. Other infections reported to occur in
conjunction with AGU include CMV (n = 4), paratyphoid fever (n = 1) and influenza A (n = 1).
Diagnosis of CMV was made based on culture (in one case report) and by serologic markers in
three other cases (3,26,27).
Hormonal changes may play a role in vulvar ulcers. Women with progesterone autoimmune
dermatitis develop painful, necrotic ulcers that recur in the late luteal phase of the menstrual cycle
when endogenous progesterone levels are high (28–30). A prospective case series of young women
found no association between ulcers and menstrual cycle. However, authors noted that 25% (5 of
20 cases) occurred in pubertal premenarchal females, and another five cases within the first year
after menarche, which may be a state of estrogen dominance (3).
Other noninfectious causes of vulvar ulcers include drug reactions, Crohn’s disease, Behçet’s
disease, and idiopathic aphthosis. A variety of drugs can cause skin or mucosal ulcers, and one
case of AGU has been reported after the use of a nonsteroidal anti-inflammatory drug (31). No
drug exposures predated onset of vulvar ulcers in a prospective series of 20 young women (3).
The vulvar manifestations of inflammatory bowel disease such as Crohn’s disease are
characterized by “knife cut” ulcers or fissures, usually located in the inguinal, gluteal and
interlabial folds, and may predate GI tract involvement (FIG. 7) (32,33). Fistulous tracts from
Crohn’s disease may resemble ulcers, but close examination reveals the tract itself (FIG. 8). In
addition, HIV, cyclic neutropenia, periodic fever, aphthous stomatitis, pharyngitis, adenitis
(PFAPA syndrome), and mouth and genital ulcers with inflamed cartilage (MAGIC syndrome)
may be associated with mucous membrane aphthae (34–36). Histiocytosis X may also present as
vulvar ulcers (37–39). Leukemia and other malignancies may have similar vulvar manifestations
(40,41). Behçet’s disease is a multi-organ inflammatory disorder characterized by recurrent oral
and genital aphthae with potential for severe morbidity.
Ulcers are deep and painful and heal with scarring (42). Although rare in the United States,
Behçet’s is seen worldwide, most commonly in Turkey and along the Silk Road. The International
Study Group criteria for the diagnosis of Behçet’s disease include recurrent oral ulcers plus at least
two of the following: recurrent genital ulceration; uveitis; skin lesions such as erythema nodosum;
or a positive pathergy test (43). Patients may also develop arthritis, gastrointestinal lesions,
vasculitis, and central nervous system involvement. Because of the absence of a diagnostic
confirmatory test, it may take 6–8 years from development of the first ulcer to establish a diagnosis
of Behçet’s disease (44). Vulvar aphthosis is another etiology that should be included in the
differential diagnosis of vulvar ulcers, although it is a diagnosis of exclusion (3). A number of
dermatologic vulvar specialists believe that by definition, Lipschutz ulcer is a variant of aphthosis.
Although vulvar aphthae are rare, oral aphthae (often known as canker sores) affect 30–66% of
adults, and up to 25% of adults report recurrent outbreaks (45). Oral aphthae are painful, shallow
ulcers with a gray-white base. Minor aphthae are small (<5 mmin diameter) and heal in 7–10 days.
The prevalence of oral aphthae is
highest in whites and adolescent girls (46). The risk factors for oral aphthosis are unclear, but they
include stress, infections, vitamin B12 and folate deficiency, and family history (47). Major
aphthae are larger (>1 cmin diameter) with a longer time to healing and are also known as
“periadenitis mucosa necrotica recurrens.” The term “complex aphthosis” describes patients who
have recurrent oral and genital ulcers but who do not meet diagnostic criteria for Behçet’s disease
(34). Complex aphthosis can further be classified as primary (idiopathic) or secondary due to
another illness (48,49).

Evaluation
Farhi et al. coined the term AGU (2), and we prefer to use this term rather than Lipschutz ulcer.
Women with AGUrequire a thorough evaluation by an experienced clinician, pain relief, and
reassurance (Table 2). The workup should start with a sensitive sexual history, which is performed
confidentially and includes questions on sexual activity and potential abuse. The review of systems
should include queries to uncover other systemic illnesses, with particular attention to ocular,
neurologic, gastrointestinal, and genitourinary symptoms.
The clinician should perform a full physical examination looking for oral and skin lesions. Of note,
because of the patient’s severe discomfort, we do not routinely attempt a speculum examination.
Although vaginal lesions may be present, documenting them does not change the patient’s
management and thus a speculum exam is not recommended unless the patient requires general
anesthesia for evaluation (3). Laboratory evaluation should always include a viral culture or PCR
of the lesion to exclude HSV infection. Because of the limited sensitivity of viral culture, PCR is
preferred.
For comprehensive evaluation, diagnostic testing for syphilis, chancroid and lymphogranuloma
venereum should be considered although the prevalence of these infections will vary by
demographics.
A complete blood count may detect anemia, neutropenia, or thrombocytopenia, which may lead to
the diagnosis of an underlying disorder (2,3). Serologic testing for EBV is indicated; however,
routine CMV serologic testing may be less useful. These results may be helpful in reassuring
patients and counseling them about future recurrences. Serologic testing for HIV should be based
on local prevalence data. Because the histopathology and microbiologic testing may be nonspecific
(see earlier discussion), we do not routinely recommend these diagnostic tests for a first episode
of uncomplicated AGU. When diagnostic tests are negative, the patient fits the clinical criteria for
Lipschutz ulcers (2–4).
In contrast to women with an isolated first episode of AGU, women with recurrent genital ulcers
or those with both oral and genital aphthae are designated as having complex aphthosis. These
women require a thorough history, mucocutaneous examination, and laboratory studies to rule out
underlying diseases including Crohn’s disease, Behçet’s disease, HIV, PFAPA syndrome, MAGIC
syndrome, and folate deficiency. Suggested labs include iron, folate, and vitamin B12 levels, and
a biopsy of the vulvar lesion may be indicated. Furthermore, consultations with gastroenterology,
rheumatology, neurology, and ophthalmology are recommended when indicated (50). If the
evaluations are normal, these patients may be deemed to have primary complex aphthosis.
Halvorsen and coll. in 2006 [25] made a review of 26 case reports in the literature of acute
genital ulcerations in virgins or nonsexually active girls, with diagnosis of EBV infection, by
serologic diagnosis of IgG and IgM for VCA (viral capside antigens) in most cases, while in 5
cases virus had also been identified from the ulcer by PCR or culture [17, 21, 24]. In these
patients serum immunoglobulin levels are not generally checked, even though secretory IgA has a unique role
in mucosal immunity, including the genitourinary mucosa [18]. Selective immunoglobulin A (IgA) deficiency is the
most common primary immunodeficiency, defined as a decreased serum level of IgA in the presence of normal
levels of other immunoglobulin isotypes [19]. A serum IgA level of less than 0.07 g/L is considered as selective IgA
deficiency, a serum IgA level higher than 0.07 g/L but two standard deviations below the normal range for age, is
referred to as partial IgA deficiency. Most individuals with IgA deficiency are asymptomatic and identified
coincidentally.

The histologic picture is of no diagnostic value.8 The upper part of the edematous corium reveals dilate
capillaries with lymphocyte,1 histiocyte, plasmocyte, and fibroblast infiltration. Proliferation and
local thickening of the vessel wall were also observed. In advanced cases infiltration mainly contains
polymorphic neutrophils, with subsequent formation of a miliar pseudoabscess and ulceration.

Treatment
Treatment of AGU is supportive. It is important to emphasize the non-sexual transmission of the disease and
patients also should be informed about the self-limiting nature of the syndrome. The goals of treatment are to
provide pain relief, improve healing, and prevent scarring. Because of this condition’s unclear
etiopathogenesis, the therapy is mainly symptomatic. Bedrest is of importance. If an underlying illness
is found, treatment should be directed to the specific etiology. Antiviral agents, such as
acyclovir, are effective only in cases of documented HSV infection (2,3). In the acute gangrenous
forms, wide spectrum antibiotic therapy proved to be beneficial. It should, however, be emphasized that
due to the hyperacute character of the disease, its course can be affected only in a limited way after the
onset. In severe forms resembling Behçet’s syndrome, steroids and colchicin therapy should be
considered. The use of externally applied disinfectants and ointments stimulating epithelialization is
worthwhile. Topical agents, oral corticosteroids, antibiotics, and anti-inflammatory agents are
advocated for the treatment of oral aphthosis (47,51,52). However, there is a paucity of literature
regarding the treatment of vulvar aphthae. The treatment recommendations provided in this
article are based on the literature for oral aphthosis treatment as well as the authors’ clinical
experience (Table 3).

Empiric treatment, such as Sitz baths, may provide pain relief and gently remove adherent necrotic
material. Topical viscous lidocaine and sucralfate have been recommended for oral aphthae
(45,50). A mixture of lidocaine, epinephrine, and tetracaine (LET) is available at the authors’
center and is safe for laceration repairs (53). LET is effective for local pain control in AGU (3).
Adequate pain control may require narcotics. If pain control cannot be achieved in the outpatient
setting, hospitalization is indicated. For oral aphthosis, studies report improved healing with
topical amlexanox paste, as well as topical and intralesional steroids (50,54). Topical amlexanox
and topical corticosteroids are welltolerated by patients with vulvar aphthosis. Some patients in
our series reported a shorter duration of pain during a second outbreak that was treated with these
agents. Intralesional corticosteroid injections (triamcinolone acetonide 10 mg/mL) can accelerate
healing of large oral aphthae. Women may be reluctant to undergo intralesional injection of vulvar
lesions.
As empiric therapy for the first episode of AGU, the authors recommend that women alternate
applying a topical anesthetic with either a corticos-teroid cream or ointment or amlexanox paste
every four hours. Use of systemic corticosteroids is indicated if patients fail to respond to topical
agents. In one case series, 30% of women had a secondary cellulitis; broad-spectrum antibiotics
such as a cephalosporin or sulfonamide to cover skin flora should be considered.

Follow-up
It is important that women with AGU receive ongoing weekly follow-up until the ulcer(s) has re-
epithelialized and pain has resolved. Mean time to healing is reported as 16–21 days (range 5–52
days) (2,3). This time frame permits repetition of laboratory studies, i.e., convalescent serologies
for EBV or CMV. Evidence of seroconversion can support the diagnosis of an acute infection, and
these women may be at lower risk of recurrence of AGU (2).
After the ulcer has healed, yearly follow-up is necessary to rule out progression to systemic disease
such as inflammatory bowel disease or Behçet’s disease. In two case series, 23–33% of women
experienced a recurrence within a year. Six per cent were ultimately diagnosed with Behçet’s
disease (2,3). In the series from Brazil, 20% of women with non-HSV AGU met criteria for
Behçet’s disease (9).

Conclusion
When direct cytotoxic infections and specific systemic diseases for AGU have been excluded,
women meet the criteria for Lipschutz ulcers. This is consistent with the original report by
Lipschutz who postulated that adolescent females are susceptible to ulcers without an infectious
etiology (1). Like oral aphthae, vulvar aphthosis has a predilection for white and adolescent
females. There may be an immunologic, genetic, or autoimmune component that confers
susceptibility to the development of ulcers in response to external stressors such as an acute viral
illness. At present, treatment is supportive and focuses on the inflammatory and immunologic
component. Women and their families should be reassured on three main points: (i) Lipschutz
ulcers are not sexually transmitted; (ii) ulcers heal spontaneously; and (iii) most patients have no
recurrence and no long-term sequelae.