Differential diagnosis of vulval ulcers

What are vulval ulcers?

Vulval ulcers (sores or erosions) are breaks in the skin or mucous membranes of the vulva that expose the underlying tissue. They may be itchy or painful. They may produce a discharge. Alternatively, they may be completely asymptomatic.

Who gets vulval ulcers?

Any woman or girl may develop vulval ulcers, irrespective of their age, region, race, ethnicity, sexual preference or socioeconomic status (depending on the cause of the ulcer).

The global incidence of genital ulcer disease is estimated to be more than 20 million cases annually.

What causes vulval ulcers?

Vulval ulcers are the result of tissue death from focal inflammation. They may be caused by both infectious or non-infectious causes.

Infectious causes of vulval ulcers

The infectious causes of vulval ulcers include sexually transmitted infections (STIs) and non-sexually transmitted infections.

Sexually transmitted infections

STIs that can cause vulval ulcers may include:

• Genital herpes — caused by the herpes simplex virus (HSV); HSV 2 is more common than HSV I
• Primary syphilis — caused by Treponema pallidum
• Chancroid — caused by Haemophilus ducreyi
• Lymphogranuloma venereum (LGV) — caused by Chlamydia trachomatis serotypes L1 and L2
• Granuloma inguinale (donovanosis) — caused by Klebsiella granulomatis.

Non-sexually transmitted infections

Viral infections that can cause vulval ulcers include:

• Herpes simplex via autoinoculation
• Epstein–Barr virus (EBV)
• Cytomegalovirus (CMV)
• Chickenpox or herpes zoster (shingles) — caused by the varicella-zoster virus (VZV).

Bacterial infections that can cause vulval ulcers include:

• Group A streptococcal infections
• Mycoplasma.

The most common fungal infection that can cause vulval ulcers is vulvovaginal candidiasis.

Non-infectious causes of vulval ulcers

Non-infectious causes of ulceration of the vulva include aphthosis, inflammatory diseases, blistering diseases, and malignancies.

Vulval aphthosis

After herpes simplex, aphthosis or non-sexually acquired genital ulceration is the second most common cause of vulval ulcers, with the highest rates occurring in Caucasians and adolescents.

Other names for vulval aphthosis include vulval aphthous ulcers, Lipschütz ulcer, Mikulicz ulcer, Sutton ulcer, and ulcus vulvae acutum. Vulval aphthosis is commonly associated with oral ulceration.

Aphthous vulval ulcers may be reactive — following an infection (such as infectious mononucleosis) or trauma — or be related to an underlying systemic disease such as:

• Crohn disease
• Behçet disease
• Gluten enteropathy (coeliac disease)
• Systemic lupus erythematosus
• Human immunodeficiency virus (HIV) infection
• Myeloproliferative disorder.

Inflammatory diseases

A range of autoimmune disease and autoinflammatory diseases may present with vulval ulceration. These include:

• Dermatitis — due to scratching or secondary infection
• Erosive lichen planus
• Lichen sclerosus
• Fixed drug eruption — most commonly caused by non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, sulfonamides, and tetracyclines
• Stevens–Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN)
• Crohn disease — typically presents with linear ulcers
• Systemic lupus erythematosus
• Darier disease
• Pyoderma gangrenosum
• Hidradenitis suppurativa.

Blistering diseases

Autoimmune blistering skin diseases may present with erosions and ulcers. The vulva is rarely the only site affected.

• Pemphigus vulgaris is a non-scarring erosive disease. The oral mucosa, vulva, anus and scalp are common sites of involvement.
• Mucous membrane pemphigoid (cicatricial pemphigoid) causes chronic ulceration and scarring. It usually affects more than one mucosal site including the vulva, anus, mouth, eyes, nostrils, and may also involve the scalp.
• Bullous pemphigoid produces tense bullae (fluid-filled blisters) on normal skin or, more often, eczematous or urticated plaques. It rarely involves mucosal surfaces but is common in the body folds (ie, the backs of knees, the inside of the armpits, the elbows and the groin) in older people.
• Erythema multiforme is an acute or recurrent reactive condition. Erythema multiforme major can cause very painful vulval ulceration, usually associated with oral ulceration and target lesions on the distal extremities.

Genetic diseases can present with chronic ulceration of vulval and perianal skin.

• Epidermolysis bullosa is a group of disorders that present with blistering in childhood. Subtypes of epidermolysis bullosa that may cause vulval ulcers include junctional epidermolysis bullosa and dystrophic epidermolysis bullosa.
• Familial benign chronic pemphigus (Hailey–Hailey disease) presents in early adult life with chronic, symmetrical maceration and erosions of the vulva, perianal skin, and other flexures, including under the breasts and neck.

Malignancy

Malignancies that can cause ulceration of the vulva include:

• Squamous cell carcinoma
• Vulval intraepithelial neoplasia (vulval squamous intraepithelial lesions).

Less commonly, the following can also cause ulceration of the vulva:

• Extramammary Paget disease
• Basal cell carcinoma
• B-cell lymphoma
• Leukaemia cutis
• Langerhans cell histiocytosis (histiocytosis X).

What are the clinical features of vulval ulcers?

Vulval ulcers are often grouped by the following features:

• Single or multiple
• Painful or painless
• Evolution of the ulcer (ie, initial appearance and progression)
  • Ulceration preceded by dryness, scaling, and excoriations is suggestive of dermatitis
• Frequency of episodes
  • Recurrent ulcers may suggest HSV, Behçet disease, fixed drug eruption
• Associated signs or symptoms
  • Inguinal lymphadenopathy indicates a likely infection
  • Uveitis, arthritis and/or a family history of these may suggest Behçet disease
  • Exposure to new medication may indicate a fixed drug eruption
  • Oral mucosal involvement occurs in aphthosis or erosive lichen planus
  • Dysuria may be due to the location of the ulcer or to sexually-transmitted urethritis
  • Constitutional symptoms may occur in herpes simplex, secondary syphilis, LGV, or systemic lupus erythematosus.

Typical characteristics of various presentations with vulval ulceration are described below.

Herpes simplex virus

• Clusters of small blisters coalesce and open to form painful (or itchy) ulcers with a red base.
• Ulcers may occur on the vulva, cervix, vagina, perineum, legs or buttocks.
• Atypical, extensive or long-standing disease affects patients with immunosuppression.
• Large, tender inguinal lymph nodes and 'flu-like symptoms occur with a primary infection.

Chancroid

• Single or multiple, unilateral, painful papules become pustular and ulcerate.
• Ulcers display ragged undermined edges with grey or yellow discharge.
• As the disease progresses, approximately 50% of patients develop tender inguinal lymph nodes that may rupture and weep.

Primary chancre of syphilis

• There is a single, painless ulcer with a clean base and firm raised edges.
• It is often associated with large, non-tender inguinal lymph nodes.

Lymphogranuloma venereum

• There is a single, transient, painless ulcer.
• It is often associated with urethritis and followed by tender inguinal lymph nodes weeks later.

Granuloma inguinale

• There are single or multiple, chronic, red, indurated, painless ulcers that bleed easily.

Aphthosis

• There are intensely painful, punched-out ulcers, which are often bilateral, with a yellow-white base and red borders.
• There is associated labial swelling, intense pain and dysuria and sometimes, large tender inguinal lymph nodes.
• Recurrent episodes of ulceration on the genital and oral mucosa associated with uveitis is suggestive of Behçet disease.

Crohn disease

• Mixed inflammatory lesions, fissures, and ‘knife-cut’ ulcers of variable severity are found.
• Deeper ulcers may progress into fistulae; most commonly, in perianal or rectovaginal sites.
• Marked painless vulval oedema may occur.

Pyoderma gangrenosum

• A tender inflammatory pustule rapidly evolves into a deep purulent ulcer with violaceous undermined borders and possible satellite lesions.
• Often precipitated by a minor injury at the site of ulceration.

Hidradenitis suppurativa

• Presents with pseudocysts, inflammatory nodules, draining sinuses and abscesses.
• Ulceration can be associated with pyogenic granuloma-like nodules.
• The skin on the labia majora, mons pubis, thighs, buttocks and below the armpits and breasts can be affected.

Squamous cell carcinoma

• An enlarging, irregular red, pink or white nodule or plaque that has wart-like and/or ulcerated surface.
• Squamous cell carcinoma may arise within intraepithelial neoplasia, lichen sclerosus, erosive lichen planus or normal skin.

How are vulval ulcers diagnosed?

Diagnosis of vulval ulceration involves taking a careful history and performing a physical examination to assess the risk of STIs, guide appropriate investigations, and determine the need for empirical therapy.

It is important to consider that:

• More than one cause may coexist
• There are varied presentations of disease, thus clinical appearance alone may be misleading
• Individuals with immunosuppression may have atypical presentations.

No pathogen is identified in up to 25% of patients; however, the aim of initial investigations is usually focused on diagnosing STIs. Patients should, as a minimum, have the following investigations:

• Viral swabs from the genital lesion for HSV polymerase chain reaction (PCR)
• Bloods for syphilis serology.

Since co-infections are common and many STIs are asymptomatic, patients with recent unprotected sexual contact should also be tested for non-ulcerative STIs via:

• Urine PCR for chlamydia and gonorrhoea
• Bloods for HIV, and hepatitis B and C serology.

The geographic location of the STI acquisition, the individual’s sexual and travel history, and the local prevalence of chancroid, LGV and granuloma inguinale should be considered prior testing for these STIs.

In patients with a low risk of STIs or in those who have had negative results, depending on the clinical presentation, it is reasonable to consider:

• Bacterial swabs for gram staining, and bacterial and yeast culture
• Viral swabs for VZV PCR
• Bloods for:
  • HSV (HSV 1 and HSV 2), EBV (immunoglobulins M and G) or a Monospot test, CMV, and mycoplasma serology
  • A full blood count, C-reactive protein, and antinuclear antibody testing
  • Testing for HLA-B51 if Behçet disease is a possibility.

A biopsy may be necessary if:

• A diagnosis cannot be made by non-invasive methods
• The ulcers do not resolve after standard therapy
• Lesions are suspicious for an underlying disorder or malignancy.

What is the treatment for vulval ulceration?

General measures

Whatever the cause, patients with vulval ulcers may need education, reassurance and symptom relief.

Affected individuals can:

• Minimise irritants (no soaps, douches, pads, tight underwear or clothing)
• Consider using spray bottles or voiding in a bath to reduce pain on passing urine
• Try salt baths
• Apply cool compresses (eg, a flannel soaked in cold water)
• Use bland barrier ointments (eg, petrolatum, zinc oxide)
• Apply a topical anaesthetic (eg, lignocaine gel, lignocaine/prilocaine cream)
• Use oral analgesics (paracetamol, NSAIDs) as required.

Oral antihistamines may also be beneficial in certain cases.

Note: severe pain and urinary retention may require hospitalisation and catheterisation.

Specific treatment

Treatment of infectious causes may include:

• Oral aciclovir, famciclovir or valaciclovir for herpes simplex or zoster
• Intramuscular penicillin G (benzylpenicillin) for primary syphilis
• Intramuscular ceftriaxone or oral azithromycin, ciprofloxacin or erythromycin for chancroid
• Oral doxycycline for LGV and granuloma inguinale.

Note: empirical treatment is initiated when there has been a known exposure to an STI, genital ulcers are suggestive of HSV, there is a high risk for syphilis, or when failure follow-up for treatment is likely.

Treatment of non-infectious causes may include:

• Topical corticosteroids or intralesional corticosteroids
• Oral corticosteroids
• Antibiotics or antifungal agents in cases of secondary infection
• Immunomodulatory agents such as methotrexate, topical or systemic ciclosporin
• Referral to appropriate specialists (eg, rheumatologist, dermatologist, gynaecologist, sexual health physician, infectious disease physician).

Note: many conditions involving vulval ulceration require a multidisciplinary approach.

What is the outcome for vulval ulceration?

The prognosis of vulval ulcers depends on the cause.

• Most STIs can be cured quickly with appropriate treatment.
• HSV cannot be cured, but recurrences can be controlled with early recognition and antiviral prophylaxis. The severity and frequency of episodes may decrease over time.
• Non-sexually acquired genital ulcers generally self-resolve without scarring within 2–6 weeks.

If left untreated, vulval ulcers can have serious health implications, including:

• Increased risk of HIV transmission for sexually active individuals
• Persistent latent infection of untreated syphilis, resulting in occult transmission to sexual partners and progression to secondary or tertiary syphilis
• Risk of STI transmission to a fetus in pregnancy or to a neonate during birth
• Scarring, adhesions or destruction of vulval architecture in erosive lichen planus, lichen sclerosus, Behçet disease, mucous membrane pemphigoid (cicatricial pemphigoid), pemphigus vulgaris, erythema multiforme major, epidermolysis bullosa and hidradenitis suppurativa
• Increased risk of malignancy in areas affected by severe inflammation such as erosive lichen planus, lichen sclerosus, and occasionally chronic hidradenitis suppurativa
• Ongoing psychosocial distress.