Fluorouracil does not improve the outcome of imiquimoid treatment of vulval intraepethelial neoplasia.

Sir, Vulval intraepithelial neoplasia (VIN) is a form of squamous cell carcinoma (SCC) in situ. The condition presents as smooth or warty plaques on the vulva which are either erythematous or white in colour. The lesions can be asymptomatic or cause pruritus, vulval pain or sexual dysfunction. The disease is often multi-focal and almost always associated with human papilloma virus (HPV) type 16 (1). The incidence of VIN is rising (2), and it is becoming a therapeutic challenge because it is more resistant to standard treatments that cure most forms of cutaneous SCC in situ (Bowen’s disease). An association with oncogenic HPV types (e.g. 16 and 18) may explain this difference (3). VIN is segregated into three types (I– III) reflecting an increasing progression of trans-epidermal dysplasia. Severe VIN (III) is premalignant, but a transformation to SCC can take many years. In contrast, VIN I is much easier to treat, but recurrences still occur in all three types. In one retrospective study of 23 genital SCCs in women, 2 were associated with VIN III; however, the majority were associated with chronic lichen sclerosis et atrophicans or lichen planus (4). Standard VIN treatments include 5-fluorouracil (5FU) cream, photodynamic therapy, CO2 laser ablation, cryotherapy and excision. Wide surgical excision – the gold standard treatment – is often complex, disfiguring and expensive (5), but despite this, surgical margins are often positive and high recurrence rates are common. One prospective study of VIN III showed a recurrence rate of 46% post-excision with positive histological margins and a 17% post-excision recurrence with negative histological margins at 7 months follow-up (6). Imiquimod (IMD) 5% cream has been used as a single treatment agent in four published studies and one case report (7–11) (Table I). The most favourable study showed that eight patients with VIN II or III (61%) had a complete regression (9). IMD enhances the development of protective innate antiviral and anti-tumour responses. It induces the local production of interferon-a and tumour necrosis factor and 2’5-oligoadenylate synthetase that confers antiviral protection and it stimulates natural killer cell activity (3, 12). 5-FU targets thymidylate synthase in tumour cells. Its selectivity for neoplastic and dysplastic cells relies upon increased DNA and RNA incorporation of 5-FU by the target cells (13). In this prospective open study we assessed the efficacy of initial treatment with IMD cream followed by 5-FU cream. Any residual VIN or SCC not eliminated by IMD should be targeted by the 5-FU cream. Cure rates were anticipated to be higher than those previously published, where IMD was used alone.