An unusual hypertrophic genital mass lesion—A diagnostic and treatment dilemma

Case presentation 

A-38-year old HIV infected South African women presented with an exophytic vulval mass measuring 8cm by 8cm (see Fig. 1). The patient was receiving highly active antiretroviral treatment (HAART), viz. efavirenz, stavudine and lamivudine for a few months and her CD4 count at that time was 188cells/μl. The vulval mass was present prior to starting HAART.

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Fig. 1. Hypertrophic vulval mass.

A punch biopsy of the vulval lesion was performed and histology revealed ulcerated skin with no evidence of dysplasia, invasive malignancy or tuberculosis. The patient also had cervical intraepithelial neoplasia 3 (CIN3) and human papilloma virus (HPV) infection as evidenced by a papanicoloau smear and cervical histology. No vulval warts were seen. A cervical large loop excision of the transformation zone (LLETZ) biopsy was performed and subsequent papanicoloau smears were negative for intraepithelial lesion or malignancy.

The punch biopsy of the vulval lesion was submitted for virological testing.

The histological features found in the biopsy sample are seen in Fig. 2.What further virological differential diagnosis would you consider and how would you investigate this patient?What treatment would you consider based on your suspected diagnosis?

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Fig. 2. Histology of vulval biopsy with immunohistochemical staining (inset).

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Evidence-based opinion

What further diagnosis would you consider and how would you investigate this patient?

The differential diagnoses of fungating vulval lesions in an HIV infected patient includes intraepithelial neoplasia, malignancies, e.g. kaposis sarcoma, warts, tuberculosis, viral infections and immune reconstitution syndrome.

Atypical lesions have been described in patients with AIDS and in those with complete immune restoration on HAART with normal CD4 counts.1, 2 Virological causes of a vulval mass lesion would include HPV, Cytomegalo virus (CMV) and herpes simplex virus (HSV) infection. HSV as a cause of a vulval mass lesion in an HIV infected patient is often not considered. Genital lesions due to HSV are common in HIV patients. Typically, these lesions present as ulcers which may persist for more than a month.1 However, atypical, fungating vulval lesions due to HSV are rare but have been reported.1, 2, 3, 4, 5, 6

HSV lesions may present as large fungating, hypertrophic lesions that present both diagnostic and treatment challenges and may necessitate repeated biopsies and cultures.3 In this patient, the initial punch biopsy of the vulval mass revealed herpes simplex infection. A vulval swab was positive for HSV by DNA PCR. A deep excision biopsy of the vulval lesion was performed. Two pieces of tissue, the largest measuring 1cm confirmed the diagnosis of HSV by histology. HSV syncytial giant cells were identified within the degenerating keratinocytes (Fig. 2) and lying loosely within the inflammatory exudate. Multinucleate HSV giant cells seen in the ulcer bed were confirmed immunohistochemically (inset Fig. 2). HSV DNA PCR was positive on the biopsy sample.

In a lesion, HSV may infect the superficial brittle layers of a mass lesion caused by a malignant or infectious process (e.g. vulval carcinoma, genital wart or TB). In such cases, HSV is not the primary aetiological agent and a superficial biopsy or swab which is HSV positive may be misleading and does not prove that HSV is causing the lesion. However, in this patient, a deep biopsy was performed and histology and PCR performed on the tissue confirmed the presence of HSV in the underlying lesion.

Reports of patients with unusual HSV presentations also indicate that some of the patients were co-infected with HPV.1 HPV is exclusively an intraepithelial pathogen that only replicates in stratified squamous epithelial cells and relies on the natural differentiation of basal keratinocytes. Although, HPV was found in the cervix, it was not found in the vulval lesion.

What treatment would you consider based on your suspected diagnosis?

The choice of treatment for first-episode ulcerative genital herpes is oral acyclovir. Topical acyclovir is discouraged as it is not effective. Intravenous acyclovir is used for the treatment of severe mucocutaneous genital herpes or systemic infection with herpes simplex which is often seen in immunocompromised patients.7

This patient was started on a course of oral acyclovir 500mg qid for 7 days but there was no improvement in the lesion. A subsequent course of valacyclovir 500mg bd for 14 days also showed no improvement. The patient was then admitted and started on intravenous (IV) acyclovir 10mg/kg 8 hourly for 14 days and a moderate improvement of a 1cm reduction in the size of the lesion was noted. The patient also reported a significant reduction in pain caused by the lesion. The patient's CD4 count at this time was 870cells/μl and she was otherwise clinically well. Due to social circumstances the patient refused further inpatient treatment. She was therefore treated with oral valacyclovir 500mg bd for a week and oral acyclovir 500mg 5 times a day for a further 2 weeks.

On subsequent follow up visits it was noted that the lesion had increased in size and the patient reported an exacerbation of pain.

The treatment of hypertrophic, fungating lesions due to HSV may prove more challenging than the treatment of ulcerative genital HSV lesions. Previous reports of treatment indicate that oral acyclovir is not effective in the treatment of hypertrophic lesions due to HSV.2, 8 This may be related to the poor bioavailability of oral acyclovir and the difficult dosing schedule where treatment needs to be taken 5 times a day. Other forms of therapy have included the use of imiquimod6 and surgical excision with oral acyclovir.1 Studies have suggested that hypertrophic genital lesions due to HSV may be related to acyclovir resistance.1, 2 In this case study, a moderate response was seen when intravenous acyclovir was used. Treatment with oral acyclovir did not show any response.

The full impact of 3–4 weeks of acyclovir could not be assessed in this patient.

However, it was noted that there was an initial favourable response to 2 weeks of IVI acyclovir and an exacerbation of symptoms when the IV acyclovir was replaced by oral therapy. This suggests that IV acyclovir may be used for the treatment of hypertrophic mass lesions due to HSV.

Atypical hypertrophic vulval lesions caused by HSV present a diagnostic and treatment challenge. Based on experience of this case, a deep biopsy of unusual hypertrophic mass lesions may assist in making the diagnosis of HSV and intravenous acyclovir appears to be superior to oral acyclovir in the treatment of such lesions.