Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Describe the less commonly occurring causes of vulvar ulcers in girls and women.

2. Differentiate uncommon vulvar ulcers from those generally seen in routine gynecologic practice.

3. Explain diagnosis and treatment of uncommon vulvar ulcers.

This article is the second of 2 parts.

Vulvar ulcers are frequently seen not only by gynecologists but also by pediatricians, family practitioners, and emergency department physicians. They present in girls and women of all ages as painful intact or unroofed blisters, often of abrupt onset. They can lead to such severe discomfort as to make urination impossible. Although the most common cause of such ulcers is herpes simplex virus (HSV) types I and II, there are multiple other, less frequently encountered etiologies for such lesions that must also be considered. While serologic testing, cultures, and biopsies play an important role in the diagnosis of these lesions, a careful history and physical examination remain the most important factor in arriving at an accurate diagnosis. This second article in the series on vulvar ulcers reviews these rarer causes of vulvar ulcers.

Behcet Syndrome

Behcet syndrome is a complex vasculitis with diverse symptoms affecting many areas of the body. It is most frequently seen in young adults ages 20 to 40 years. There is a geographic propensity for Behcet disease in individuals from the Middle East, Turkey, and Eastern Asia.1

The vasculitis that produces Behcet syndrome's multiorgan involvement affects vessels of all calibers: small, medium, and large. It most frequently manifests itself as recurrent, painful ulcers of the mouth and genitals surrounded by an erythematous rash (Figure 1).2,3 In addition to involvement in other organ systems (skin, eye, gastrointestinal tract, joints, and both central and peripheral nervous system), Behcet large vessel vasculitis can lead to pulmonary artery aneurysms and life-threatening pulmonary hemorrhage.

Figure 1. Vulvar Behcet ulcer. (From Maia et al,

The diagnosis of Behcet syndrome is largely clinical: recurrent ulceration of mouth and/or genitals, frequent involvement of other organ systems, and alternative etiologies having been excluded. Although there is often an elevation of markers of systemic inflammation-erythrocyte sedimentation rate and C-reactive protein-these are not diagnostic.

Treatment is aimed at suppressing recurrences of skin ulcerations and treating symptomatic involvement of other organ systems. For oral and genital ulcers, corticosteroids should be applied 3 to 4 times daily until the lesions resolve. Other medications employed by specialists for more complex manifestations include colchicine, thalidomide, and pimecrolimus. Short-term topical anesthetic therapy is sometimes necessary to control pain from the lesions. Colchicine 1 to 2 mg every day has been found to be effective in decreasing the frequency of recurrences.4

Crohn Disease

A relatively common inflammatory bowel syndrome, Crohn disease is the most common gastrointestinal condition causing vulvar ulcerations, abscesses, fistulae, and lymphedema. "Knife-cut" shallow ulcerations can be seen in the vulvar skin folds (Figure 2).5 Symptoms of these lesions range from minimal discomfort to intense pain and may occur even before gastrointestinal symptoms appear.

Figure 2. Crohn disease vulvar lesions. (From Shields et al,

While Crohn's-related fistulae and abscesses can be seen anywhere on the vulva, they are most common in and around the anus. Vulvar lesions first appear as red papules or small nodules that can develop into fistulous tracts surrounded by friable granulation tissue.6

Diagnosis is made by the pattern of the lesions and the patient's history of Crohn disease. Skin biopsy can support the diagnosis.

Treatment starts with optimal control of the underlying Crohn disease; and should be supported by comfort measures such as warm compresses, soaks, lidocaine jelly or ointment, and pain medication. Catheterization is sometimes required for bladder emptying. Other medical treatments can include sulfasalazine or other aminosalicylates; glucocorticoids; immunomodulators such as methotrexate and azathioprine; and biologic therapies (eg, infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab, and ustekinumab.) 7

Lipschutz Syndrome

Lipschutz syndrome, or nonsexual acute genital ulceration, manifests as painful ulcerations (Figure 3).8 These lesions appear spontaneously on the vulva of girls and young women who are not yet sexually active. They often occur several weeks after a systemic flu-like viral illness, most frequently with Epstein-Barr virus. There are recent reports of Lipschutz lesions after COVID-19 vaccination and infection.9 The lesions are extremely painful, often making urination difficult, and sometimes requiring bladder catheterization. The ulcers are usually multiple, bilateral (often with "kissing" lesions), and are frequently deeper and wider (1-3 cm) than typical HSV ulcers. They have a necrotic base covered with an exudate, which subsequently dries into a blackish crust. Usually there is accompanying lymphadenopathy and often an elevation of liver enzymes. Although the lesions resolve spontaneously over 2 to 6 weeks, one-third of patients will experience recurrences.10

Figure 3. Lipschutz ulcer.

This condition is significant both because of the distress it causes the girls and young women it affects and, perhaps most importantly, because it is relatively unknown to clinicians and therefore often is misdiagnosed. This can lead to individuals who present with Lipschutz ulcers being assumed to have HSV-and to have acquired it by sexual contact, much to the distress of patients and family who adamantly deny any such activity.

The diagnosis is one of exclusion. The key elements of diagnosis are first believing a patient's history of not having had sexual contact and next ruling out herpes simplex by polymerase chain reaction (PCR). Other sexually transmitted infectious causes of vulvar ulceration-syphilis, lymphogranuloma venereum (LGV), granuloma inguinale, and chancroid-are extremely unlikely in this age group in individuals with no history-or no recent history-of sexual contact. Although Behcet syndrome, inflammatory bowel disease, and autoimmune bullous diseases must be ruled out, the age of patients presenting with Lipschutz syndrome symptoms and the absence of oral, bowel, dermatologic, or ophthalmic conditions are usually sufficient to exclude these possibilities.

Performing serology testing for Epstein-Barr virus, cytomegalovirus, and Mycoplasma pneumoniae may help confirm the diagnosis. Skin biopsy is usually nondiagnostic and need not be performed.

There is no antibiotic or other specific treatment for Lipschutz syndrome. Therefore, treatment consists of comfort measures as described above; topical, high-potency corticosteroids to reduce inflammation; and systemic corticosteroids in patients with severe symptoms unresponsive to the above measures.

Syphilis

Syphilis is a sexually transmitted infection caused by the spirochete Treponema pallidum. Once a relatively common venereal disease, it is now seen mainly in special populations (ie, men who have sex with men or sex workers and their clients). Although currently 80% of new cases of syphilis are diagnosed in men,11 infections in women are especially dangerous because of the potential for the development of congenital syphilis in their offspring. Frequently, syphilis and HIV are seen together.

Infection is generated by contact, usually oral or genital, with the syphilitic lesions of one's sex partner. The rate of acquisition after contact is approximately 30%.12

The course of untreated syphilis has 3 stages. Evidence of initial infection-primary syphilis-first appears approximately 3 weeks after exposure. The initial lesions are papules that over several days lose their epithelial covering to become 1- to 2-cm-wide, painless ulcers with edematous edges called "chancres" (Figure 4).13 They can appear at any site of contact with the infectious agent: genitals, anus, mouth, or skin. Vulvar lesions are usually accompanied by bilateral inguinal lymphadenopathy. Chancres spontaneously resolve in 3 to 6 weeks-but infectious spirochetes remain active and, if untreated, spread systemically, leading over time to secondary and tertiary syphilis.

Figure 4. Syphilitic chancre. (From Hicks and Clement,

Secondary syphilis develops 6 weeks to 6 months after the initial infection. It is marked by an erythematous macular-papular rash that covers the entire body and, almost uniquely in medicine, is present on the palms and soles. Large patches of condyloma-like growths, termed condyloma lata, are often seen in the perineal and anal areas. Secondary syphilitic lesions such as these contain high levels of infectious spirochetes. Secondary syphilis is usually accompanied by generalized fever and malaise.14

Tertiary syphilis-almost never seen in contemporary practice in the United States-becomes symptomatic after years or decades of latency and can involve every organ system. Its most common manifestations are syphilitic aortic aneurysm and osteomyelitis, tabes dorsalis, general paresis, and granulomatous "gumma" in brain, heart, skin, and bone.15

Two types of tests are used to screen for and diagnose syphilis: nontreponemal and treponemal-specific tests. Nontreponemal tests measure the reaction between a patient's serum and a cardiolipin-cholesterol-lecithin antigen. The 2 most commonly used nontreponemal tests are the rapid plasma reagin and venereal disease research laboratory tests. Titer levels of these tests are also used to follow treatment effectiveness.16

Although nontreponemal tests are inexpensive and easy to perform, they are subject to high rates of false positivity and less than optimal sensitivity. The nontreponemal test will be negative 20% to 30% of the time when a patient has a positive treponemal-specific serologic test and even a visible chancre.17 Thus, individuals with either positive or negative nontreponemal results where there is a high index of suspicion should have their results followed up by the more sensitive and specific treponemal tests.

Direct treponemal tests detect antibodies specific to syphilis. Although there are several types of treponemal tests, the classic fluorescent treponemal antibody absorption (FTA-ABS) test is 84% sensitive for detecting primary syphilis and even more sensitive (96%) for more advanced stages.18 However, this long-standing testing paradigm is in flux. There are now multiple direct treponemal tests (T. pallidum particle agglutination test, microhemagglutination assay for T. pallidum, enzyme immunoassay, and chemiluminescence assay), which various advocates say are more sensitive and specific for primary syphilis detection than the older FTA-ABS test. Some infectious disease specialists now recommend a reverse protocol, first employing the direct treponemal test, then confirming with nontreponemal assays. Finally, point-of-care rapid treponemal tests are now being deployed in various clinical settings. For instance, the Syphilis Health Check (SHC) test is a fingerstick treponemal-based antibody test with a sensitivity of 87.7 % that produces results in 10 minutes and is designed for use in outpatient facilities.19 Darkfield microscopy, once a staple of venereal disease clinics, is complex, requires special equipment, and is rarely used today in developed countries.

Remarkably, treatment for syphilis has remained unchanged for three quarters of a century. Parentally administered penicillin G is still the drug of choice for all stages of syphilis with the course of treatment being longer for secondary and tertiary stages. For patients allergic to penicillin, alternatives are testing for penicillin allergy and/or rechallenging with penicillin; desensitizing to penicillin if allergy testing is positive; and use of an alternative agent with close posttreatment monitoring. These alternatives include doxycycline 100 mg orally twice daily for 14 days or ceftriaxone 1 g daily IM or IV for 10 to 14 days.20

An acute febrile response, termed the Jarisch Herxheimer reaction, is often noted after penicillin treatment for syphilis. It is thought to be due to the release of toxins from the dying, dissolving spirochetes. Pregnant patients being treated for syphilis must be followed carefully as the Jarisch-Herxheimer reaction can lead to miscarriage and premature labor.21

With successful treatment nontreponemal test titers will resolve; recurrence will be marked by titer rise. Because treponemal tests measure syphilis antibodies, these remain positive for life even with successful treatment.

Bullous Diseases

Bullous skin conditions are infrequently seen, even by dermatologists. They occur in 12 adults per 100,000. These lesions can appear on any part of the body although they have a predilection for the arms, legs, and trunk and occur more often in older than in younger patients. Nevertheless, these bullous dermatologic conditions can affect the vulva, causing blistering lesions, which, when unroofed, become vulvar ulcers. It is thought that there is a genetic predisposition for bullous diseases, which promotes pathologic immune responses to as-yet-undefined triggers.22

Bullous Impetigo

This is a superficial bacterial infection usually due to strains of Staphylococcus aureus or Streptococcus, which produce toxins that disrupt the cell adhesion between layers of the epidermis. The resulting ulcerations develop a yellow crusty covering similar to that of facial impetigo. Although most often occurring on the body and trunk, these lesions are also often seen in girls and women on the vulva, mons, and perianal area. The lesions are differentiated from other bullous diseases by culture of staph or strep from the base of the ulcers.23

Bullous impetigo can be treated with either topical or oral therapy depending on the extent and severity of the lesions. When there are few lesions, topical mupirocin and retapamulin are the agents of choice, the former applied three times a day and the later twice a day. Other dermatologic antibiotics such as over-the-counter triple antibiotic ointments consisting of bacitracin-neomycin-polymyxin B are less effective. When systemic therapy is necessary, cephalexin or dicloxacillin is appropriate as both cover the majority of staph or strep strains found within the mucosal ulcerations.24

Bullous Pemphigoid

Bullous pemphigoid is an autoimmune disease, which presents with widespread, intensely pruritic urticarial plaques and tense, subepithelial blisters that measure 1 to 3 cm in diameter. It is usually seen in older adults (Figure 5). There is often mucosal involvement, which may involve the oral cavity, ocular conjunctiva, nose, pharynx, larynx, esophagus, anus, and genital mucous membranes.25

Figure 5. Bullous pemphigoid. (From Schmidt et al,

The pathophysiology of bullous pemphigoid involves immunoglobulin and complement deposition within the various layers of the epidermis down to the basement membrane and can be initiated by exposure to multiple medications. The most commonly implicated medications are penicillamine, furosemide, captopril, penicillin and its derivatives, sulfasalazine, phenacetin, nalidixic acid, and tumor necrosis factor-[alpha] inhibitors adalimumab and etanercept.26

The diagnosis of bullous pemphigoid is suggested by the presence of tense, severely pruritic bullae, particularly when accompanied by a history of previous episodes of the lesions, and recent initiation of a new, suspect medication. The diagnosis can be confirmed by a biopsy of the lesion both to determine its microscopic pathologic appearance and to detect circulating antibasement membrane antibodies.27

Treatment consists of a combination of anti-inflammatory medications such as topical and/or systemic corticosteroids; immunosuppressant agents such as azathioprine, mycophenolate, and methotrexate;28 and antibiotics, most notably oral doxycycline combined with nicotinamide.29 Bullous pemphigoid often has a relapsing, recurrent course that can last over many years (average 5-6) and may require intermittent treatment throughout that time.

Bullous Pemphigus

Bullous pemphigus is a rare, intense, even life-threatening bullous disease that can cause both blisters and ulcers on the vulva (Figure 6).30 It differs from pemphigoid in several important ways. First, the coverings of pemphigoid lesions are tense, whereas the membranes of pemphigus bullae are flaccid. Second, pemphigus lesions almost always involve mucous membranes in multiple areas of the body including the oral cavity, nose, esophagus, conjunctiva of the eyes, and the perineum: vulva, vagina, cervix, and anus. Third, the primary symptom associated with pemphigus is pain, while that of pemphigoid is pruritis.

Figure 6. Blisters and ulcers of bullous pemphigus. (From Hull and Zone,

The pathophysiology of pemphigus is the same as for pemphigoid: the development of immunoglobulin G (IgG) antibodies to intercellular adhesion molecules. This may occur as a response to treatment with or exposure to thiol (SH) compounds (eg, penicillamine and captopril); nonsteroidal anti-inflammatory drugs that are metabolized to thiols (eg, piroxicam); or penicillins.

The diagnosis is made by the history of a patient's recent medication usage; the appearance of the lesions, especially the flaccidity of the bullous membranes; and biopsy of the lesion for histology and immunologic testing.

Treatment consists of topical corticosteroids when the number of lesions and the associated symptoms are moderate. Systemic corticosteroids are appropriate if lesions are more numerous or symptoms more severe. Azathioprine, methotrexate, mycophenolate, and cyclophosphamide are treatment alternatives, as is dapsone, which acts as an immunomodulatory agent.31

Pemphigus may recur over many years with repeated outbreaks and remissions.32

Rare Infectious Vulvar Ulcerations

Chancroid, granuloma inguinale, and LGV are sexually transmitted diseases that are rarely seen in the United States. These formerly were known as "tropical vulvar ulcerative diseases." They mainly occur in the same population in which syphilis is diagnosed, ie, men who have sex with men and sex workers and their clients. Although these conditions must be considered in the differential diagnosis of a patient presenting with vulvar ulcers, they are seen so infrequently that most practicing gynecologists will not see them in their entire career.

Chancroid

Chancroid, an infection caused by Haemophilus ducreyi, becomes manifest 4 to 10 days after exposure. It presents initially as erythematous papules in the genital and anal areas (Figure 7).33 The papules break down within several days into multiple ulcers. These lesions are highly contagious and, if untreated, are followed by lymphadenopathy with lymph node suppuration, drainage, and occasional fistula formation. The swollen lymph nodes are extremely painful.34

Figure 7. Inguinal chancroid ulcer. (From Hicks,

There are currently fewer than 10 cases a year of chancroid reported in the United States.35 Diagnosis is dependent on culture or nucleic acid amplification testing-but these tests are rarely offered by most laboratories and specimens have to be sent to specialty, venereal disease, or Centers for Disease Control and Prevention (CDC) laboratories. Thus, the initial diagnosis is usually made clinically. Fortunately, treatment for chancroid (ie, azithromycin) is similar to that for the other two uncommon ulcerative venereal infections-lymphogranuloma venereum and granuloma inguinale. Therefore, the absence of a precise diagnosis-or misdiagnosis-is usually of little clinical consequence, and treatment should be started pending confirmation of the actual diagnosis.36 This is especially relevant, since in the population most likely to get chancroid, follow-up may be unreliable. When possible, sexual contacts of patients with chancroid or chancroid-like lesions should also be treated.

CDC-recommended treatment37 for chancroid is azithromycin 1 g orally in a single dose or ceftriaxone 250 mg IM in a single dose, with ciprofloxacin or erythromycin as alternatives. Some authorities recommend that patients diagnosed with or suspected of having chancroid be simultaneously treated for syphilis with penicillin G.

Granuloma Inguinale

Granuloma inguinale also presents with tender vulvar nodules that break down into ulcers. The ulcer bases are beefy-red and bleed easily to touch (Figure 8).38 The lesions are often painful, pruritic, and produce a foul-smelling discharge. Most characteristically, the presenting ulcers may expand and coalesce, leaving large patches of denuded epithelium on the vulva, perineum, inner thighs, and abdomen. The lesions of granuloma inguinale heal by fibrosis and often result in keloid formation.39

Figure 8. Granuloma inguinale ulcerations. (From CDC.

Similar to chancroid, definitive diagnosis of this rare condition is difficult. The current standard for diagnosis is the visualization of pathognomonic Donovan bodies-macrophages with inclusion bodies-that can be seen by microscopic examination of the biopsies of granuloma inguinale lesions. There are currently no FDA-approved PCR tests available for the diagnosis of granuloma inguinale.40

Treatment is with azithromycin (1 g once weekly, or 500 mg daily) for 3 weeks or until all lesions include healed.34 Other antibiotics that can be used for treatment include doxycycline, ciprofloxacin, trimethoprim-sulfamethoxazole, and erythromycin.41 Healing of genital ulcers may take several weeks. Ulcers may recur despite treatment.

Lymphogranuloma Venereum

Another of the uncommonly seen genital ulcer diseases, LGV, is caused by Chlamydia trachomatis. It is also mainly seen in men who have sex with men and in sex workers and their clients. Women who are infected may not be symptomatic and may carry latent disease.

Initial presentation is with transient skin lesions or shallow ulcerations that quickly resolve, only to be followed 1 to 4 weeks later by infected inguinal lymph nodes that drain pus and form sinuses; perirectal gland infection; and proctitis with bloody, pus-laden discharge (which is sometimes confused with inflammatory bowel disease).

These lesions often heal with marked scarring of involved areas, perineal-vaginal and rectovaginal fistulas, and rectal strictures (Figure 9).42,43

Figure 9. Groin abscess (

The diagnostic test for LGV is a nucleic acid amplification test for C. trachomatis using material from the lesions. However, because these tests are often not available (as is also the case with tests for the other rare vulvar ulcerative infections), diagnosis often is based on a combination of clinical suspicion, knowledge of the probability of infection in one's catchment area, and exclusion of other diagnostic possibilities to as great a degree possible.

Treatment of LGV is with doxycycline 100 mg orally twice daily for 21 days. Azithromycin 1 g weekly by mouth for 3 weeks is the recommended alternative.44 Longer courses of therapy may be necessary if there is persistent infection. Presumptive treatment is recommended if a firm diagnosis cannot be made.

Conclusion

Vulvar ulcers in girls and women are conditions that every gynecologist in general practice will see. Although most often these will be caused by herpes simplex infection, other entities have to be kept in mind, especially when the patient has been involved in high-risk behaviors or the condition does not respond as expected to standard therapy.

As always, a careful history and physical examination are vital and may quickly make the diagnosis clear. Appropriate testing should be performed to confirm the diagnosis whenever possible. Almost always comfort and hygiene measures will be necessary in addition to any specific pharmacologic treatment. Instructions will also have to be given to patients to make a maximum effort to have their sexual partners treated.

In addition to the pain and discomfort vulvar ulcerative lesions cause, there is usually a tremendous emotional overlay on the part of patients who fear-correctly or not-that they have a sexually transmitted disease that will recur repeatedly, destroy their intimate relationships, and potentially interfere with future pregnancies. Thus in treating girls and women with vulvar ulcers, clinicians need to be especially sensitive to the emotional distress their patients may be experiencing.

Practice Pearls

* History and physical examination will lead to the diagnosis of most causes of vulvar ulcers. Subsequent testing usually plays only a confirmatory role.

* Fortunately, the rarer forms of vulvar ulcers-the pemphigoids, the sexually transmitted infectious diseases of chancroid, lymphogranuloma venereum, and granuloma inguinale-are almost never encountered in routine practice. Still, they must be thought about when presented either with unusual lesions or with patients whose sexual practices place them at high risk.

* Treatment for all vulvar ulcer conditions includes comfort measures-soaks, analgesics, and often corticosteroid creams or ointments-even before more specific therapies are initiated.

* All of the "tropical" vulvar ulcerative diseases can be treated with azithromycin while awaiting the sometimes lengthy process of specific laboratory diagnosis.

* Lipschutz syndrome should be considered in any young woman with painful vulvar ulcers who denies sexual contact.

References