Genital ulceration is defined as lesions characterized by the loss of epithelium in the skin or mucosa of the genital area. A regional lymphadenopathy often accompanies the ulceration. The combination of ulceration and lymphadenopathy constitutes the genital ulcer adenopathy syndrome. The importance of genital ulcer disease has increased considerably since it became evident that these lesions may increase the risk of HIV transmission.

Genital ulcers are more common in developing countries than in the developed world. In Europe and North America, 1-5% of STI patients present with genital ulceration, whereas the comparable figure for Africa and Asia is 20-70%. The aetiology of genital ulceration also shows remarkable geographic variability. Genital herpes is by far the most frequent cause in Europe and North America, whereas chancroid is more common in sub-Saharan Africa and South East Asia. Lymphogranuloma venereum (LGV) is endemic in parts of Africa, India, South America, the Caribbean and parts of South East Asia. Donovanosis is largely restricted to Papua New Guinea, southern Africa, north-east Brazil, French Guyana and the aboriginal communities in northern Australia.

Aetiology

The most frequent infectious causes of genital ulceration are herpes simplex virus (HSV) (genital herpes), Treponemapallidum (syphilis), Haemophilus ducreyi (chancroid), the L-serovars of Chlamydia trachomatis (LGV) and Klebsiella granulomatis (donovanosis). Other causes include Behget’s and Reiter’s syndromes, fixed drug eruption, erythema multiforme, Crohn’s disease, aphthous ulcers, erosive lichen planus, trauma, candidiasis and malignancy.

Clinical features

The classical presentation of genital ulceration often does not correspond to the textbook descriptions. Diagnosis is sometimes difficult because clinical presentations are often atypical and mixed infections are common, especially in developing countries. In addition, secondary bacterial or fungal infections, application of antibiotics or corticosteroids and the presence of immunodeficiency as in HIV disease, can alter the clinical appearance of ulcers.

History

A medical history with a detailed sexual history is essential in determining the likely aetiology of genital ulcers. The likelihood of an infectious cause increases if there has been a recent change of sexual partner. Place of origin, ethnic group and foreign travel may suggest an increased risk of certain diseases (e.g. chancroid, lymphogranuloma venereum and donovanosis). Most cases of syphilis and lymphogranuloma venereum diagnosed in Europe in the past few years have been in men who have sex with men. A drug and allergy history may indicate fixed drug eruption or erythema multiforme.

The sexual history may help to identify the infection source and hence the incubation period. In general, the incubation periods for chancroid (1-14 days) and genital herpes (2-20 days) are short, whereas they are usually longer for syphilis (9-90 days), lymphogranuloma venereum (3 days to 6 weeks) and donovanosis (1-4 weeks, but up to 6 months). However, it is not always easy to identify the correct source of the infection, especially if there are multiple partners or if long incubation periods are involved. Unlike infectious ulcerations, which have incubation periods of days to weeks, traumatic ulcers usually develop quickly (within 24 hours) after the causative effect.

Pain is not a universal symptom in genital ulceration. Whereas ulcers in genital herpes, chancroid and Behcet’s are generally painful, those in syphilis and lymphogranuloma venereum are usually painless. Donovanosis ulcers are either painless or only mildly painful.

Another important question in the history is whether or not the ulcers are restricted to the genital area. Ulceration involving both genital and non-genital sites suggests non-venereal origin such as Behget’s, erythema multiforme, lichen planus or aphthous ulcers. In Crohn’s disease, the ulcers are normally associated with symptoms of bowel disease.

Examination

A presumptive diagnosis can sometimes be made by the characteristic appearance of the ulcers, their distribution and associated findings. However, these characteristics are often atypical as a result of secondary infections and mixed aetiologies. Most genital ulcers in men are found on the penile shaft, the prepuce, near the frenulum and in the coronal sulcus. In women, lesions may occur on the labia, fourchette, vagina, cervix and perianal area. Typically, the lesions of primary syphilis and lymphogranuloma venereum are solitary, whereas those of genital herpes, chancroid and donovanosis are multiple.

In genital herpes, small clusters of vesicles on an erythematous base first appear and these soon develop into multiple shallow ulcers. In syphilis, the papule develops into an ulcer with a sharply demarcated and raised edge. The base is smooth and non-purulent. In chancroid, the papules surrounded by erythema become pustules. These in turn rupture to form ulcers with ragged, undermined and irregular edges. The base has yellow-grey exudates and bleeds easily. In lymphogranuloma venereum, the small ulcers with elevated and oval edges heal quickly and often go unnoticed. In donovanosis, the lesion is indolent and progressive with a ‘beefy’ red base and granulation-like tissue. In Behget’s syndrome, the lesions begin as small papules that erode to form erythematous, punched-out ulcers. In Crohn’s disease, the ulcers are often described as deep and knife-cut.

When present, features of the associated regional lymphadenopathy may also be helpful in differentiating the different aetiologies. These include their consistency, tenderness, fluctuance and whether they are bilateral or unilateral. The lymph-adenopathy in primary syphilis is usually discrete, bilateral, firm and painless, whereas those in genital herpes are also often bilateral but are usually smaller and tender. In contrast, the lymphadenopathy associated in either chancroid or lymphogranuloma venereum is usually unilateral and tender. It may also undergo suppuration to form inguinal abscesses (buboes) and rupture. lymphogranuloma venereum usually involves several nodes, and when both inguinal and femoral nodes are swollen and divided by the inguinal ligament, this creates the classic ‘groove-sign’. The pseudobuboes in donovanosis are not due to infected lymph nodes; they are granulomatous nodules in the subcutaneous tissue of the inguinal region.

Laboratory diagnosis

A good clinical history and a thorough physical examination provide useful indications to the aetiology of the genital lesions, and can often lead to a presumptive diagnosis. In order to obtain a definitive diagnosis of genital ulceration, laboratory evaluation should be performed.

Collection of specimens

For dark-ground microscopy (diagnosis of primary syphilis), the ulcer should be washed with saline and dried with gauze. It is then squeezed between thumb and index finger until an exudate appears. This exudate should then be collected by a loop or a cover slip.

Specimens for herpes simplex virus culture are best obtained following disruption of vesicles and collection of vesicle fluid. If lesions are already ulcerated, the specimen is collected by swabbing of the base of the ulcer. Swabbing the ulcer base also provides specimens for cultures of H. ducreyi and C. trachomatis. In cases of suspected donovanosis, materials are used from scrapings obtained from the edges of the lesions or from punch biopsy. Biopsy is also indicated in atypical ulcers, in ulcers of suspected non-infectious causes (e.g. Behget’s and Crohn’s) and in cases of suspected malignancy.

When fluctuant lymph nodes (buboes) are present, needle aspiration provides specimens for cultures of C. trachomatis and H. ducreyi and for dark-ground microscopy to exclude T. pallidum.

Blood is collected for serological tests for syphilis and lymphogranuloma venereum.

Microscopy

Dark-ground microscopic examination remains the gold standard for diagnosis of early syphilis. The organism T. pallidum is recognised by its morphology and characteristic movement. However, the procedure requires a suitably adapted microscope and considerable technical expertise to discriminate between T. pallidum and other spirochetes. In chancroid, direct examination of the specimen by a Gram stain may reveal pleomorphic Gram-negative organisms in a ‘school of fish’ pattern. However, interpretation is often difficult and the test is not reliable.

In genital herpes, antigen can be detected by using immunofluorescence. However, sensitivity of this test is low and viral culture remains the method of choice. In donovanosis, diagnosis is dependent upon the demonstration of intracytoplasmic encapsulated Donovan bodies within mononuclear cells in Giemsa- or Wright-stained smears.

Culture

Viral culture is the method of choice for the diagnosis of genital herpes. Isolation of H. ducreyi from a genital ulcer or lymph node provides a definitive diagnosis of chancroid. However, culture of H. ducreyi is difficult and may not be offered by all laboratories. It is important to request culture media from the laboratory in advance so the specimen can be plated immediately after collection. Gonococcal agar base supplemented with bovine haemoglobin, foetal calf serum and vancomycin is often used.

Formerly, culture of chlamydia from lesional material was used for diagnosing lymphogranuloma venereum but its low sensitivity and limited availability is making NAAT testing more popular.

Serology

All patients with genital ulceration should have serological tests for syphilis. They may be negative when the patient presents with a chancre, but will usually become positive during secondary syphilis. Serological tests should not replace dark-ground microscopy in the diagnosis of primary syphilis, but could be used to further evaluate genital ulcers and to quantify response to treatment.

Serology is rarely useful in the diagnosis of primary herpes. In lymphogranuloma venereum, the chlamydial complement-fixation test, which measures antibody to chlamydial group antigen, is the most widely used serological test although is not specific for the L serovars.

Molecular techniques

The development of amplification techniques such as the polymerase chain reaction (PCR) has resulted in methods that are both sensitive and specific to the detection of the organisms associated with genital ulceration. They are, however, expensive, requiring special containment laboratories, appropriate equipment and expert staff. PCR is becoming widely used for the detection of herpes simplex virus and has also been used (mainly in research) to detect the presence of T. pallidum and H. ducreyi. A multiplex PCR has also been developed to detect the presence of these three organisms in a single ulcer specimen.

Nucleic acid amplification tests for C. trachomatis such as PCR and strand displacement amplification give a positive result when testing for the L serovars that cause lymphogranuloma venereum. However, further molecular tests are necessary to say precisely which serovar is involved.

Management (For the management of specific conditions, see the relevant sections.) With the exception of genital herpes, treatment is normally initiated after establishment of a definitive laboratory diagnosis. In the case of primary genital herpes, appropriate antiviral therapy should be commenced at the time of clinical diagnosis. In settings where laboratory support is limited and mixed infections are common, syndromic management can be initiated. This approach is recommended by the World Health Organisation (WHO), particularly for developing countries. With the exception of H. ducreyi, antimicrobial resistance is not yet a major problem.

In ulcers where secondary bacterial infections are present, treatment may consist simply of frequent application of warm-water compresses to remove necrotic material and purulent exudates. In severe cases, a broad-spectrum antibiotic should be given. Until syphilis can be definitely excluded, a non-treponemicidal antimicrobial such as cotrimoxazole should be used. The fluctuant buboes of lymphogranuloma venereum and chancroid should be aspirated through adjacent healthy skin to avoid fistula formation.

In fixed drug eruption and in erythema multiforme, the offending medication should be discontinued immediately. Topical corticosteroids should not be used in infectious ulcers but are useful in lichen planus, aphthous ulcers and mild Behget’s syndrome. Systemic corticosteroids may be required in erythema multiforme and in Crohn’s disease.

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