Surgery or topical therapy for vulval intraepithelial neoplasia
Authors: Sven Mahner, Linn Wölber
Journal: The Lancet Oncology (2014)

The incidence of intraepithelial neoplasia of the vulva has been rising for the past few decades,1Judson PL Habermann EB Baxter NN Durham SB Virnig BA Trends in the incidence of invasive and in situ vulvar carcinoma.Obstet Gynecol. 2006; 107: 1018-1022Crossref PubMed Scopus (343) Google Scholar possibly due to an increase of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesions, particularly in young women. High-grade squamous intraepithelial lesions (vulval intraepithelial neoplasia grade 2–3) are typically multifocal and judged to cause more than 90% of all diagnosed cases of vulval intraepithelial neoplasia. By contrast with low-grade squamous intraepithelial lesions (vulval intraepithelial neoplasia grade 1–2), which are usually self-limiting with a high rate of spontaneous regression, high-grade squamous intraepithelial lesions can progress to invasive carcinoma and are, therefore, defined as precancerous lesions. Untreated patients have a 6–9% risk of progression to vulval carcinoma.2van Seters M van Beurden M de Craen AJ Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.Gynecol Oncol. 2005; 97: 645-651Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 3van de Nieuwenhof HP Massuger LF van der Avoort IA et al.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age.Eur J Cancer. 2009; 45: 851-856Summary Full Text Full Text PDF PubMed Scopus (123) Google ScholarDifferentiated disease is another type of high-grade vulval intraepithelial neoplasia: it is less frequently diagnosed than high-grade squamous intraepithelial lesions (diagnosed in 2–10% of cases), lesions are usually HPV-negative, and the disease is typically associated with vulval lichen sclerosus.4van den Einden LC van der Avoort IA de Hullu JA Prevention, identification and treatment of vulvar squamous (pre)malignancies: a review focusing on quality of care.Exp Rev Anticancer Ther. 2013; 13: 845-859Crossref PubMed Scopus (6) Google Scholar Although HPV-negative lesions are widely accepted to have greater potential to progress to invasive disease than other lesion types (up to 30% higher),3van de Nieuwenhof HP Massuger LF van der Avoort IA et al.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age.Eur J Cancer. 2009; 45: 851-856Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar no predictive markers are known for the progressive potential of different types of vulval intraepithelial neoplasia.Standard treatment for high-grade squamous intraepithelial lesions is surgery, either cold-knife resection or laser vaporisation, which can result in substantial morbidity and potential psychosexual dysfunction.5Thuesen B Andreasson B Bock JE Sexual function and somatopsychic reactions after local excision of vulvar intra-epithelial neoplasia.Acta Obstet Gynecol Scand. 1992; 71: 126-128Crossref PubMed Scopus (57) Google Scholar The main argument for cold-knife resection over the otherwise less invasive surgical technique of laser vaporisation is possible histological detection of occult vulvar carcinoma within a preinvasive lesion. However, in a systematic review, occult invasive disease was noted in 3% of patients, who had mostly microinvasive cancers.2van Seters M van Beurden M de Craen AJ Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.Gynecol Oncol. 2005; 97: 645-651Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar This relatively low risk shifts the focus of management of high-grade squamous intraepithelial lesions away from detection of invasive cancer and towards symptom control and prevention of carcinogenesis.20–30% of patients who undergo a surgical intervention have recurrence of disease, irrespective of the treatment modality,6Hillemanns P Wang X Staehle S Michels W Dannecker C Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy.Gynecol Oncol. 2006; 100: 271-275Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar and neither cold-knife nor laser surgery can treat effectively the underlying cause of most high-grade squamous intraepithelial lesions—HPV infection.7Woelber L Kock L Gieseking F et al.Clinical management of primary vulvar cancer.Eur J Cancer. 2011; 47: 2315-2321Summary Full Text Full Text PDF PubMed Scopus (78) Google Scholar Topical treatment with the immune-modifier imiquimod is an effective alternative to surgery, with a durable complete response reported in 35% of patients and a partial response in 38%.8van Seters M van Beurden M ten Kate FJ et al.Treatment of vulvar intraepithelial neoplasia with topical imiquimod.N Engl J Med. 2008; 358: 1465-1473Crossref PubMed Scopus (266) Google Scholar Side-effects of imiquimod are pain and discomfort in the treatment area, fatigue, and headache. Therefore, alternative topical regimens with favourable toxic-effect profiles are needed.In The Lancet Oncology, Amanda Tristram and colleagues present findings of a randomised phase 2 trial of topical imiquimod and the nucleotide analogue cidofovir for treatment of vulval intraepithelial neoplasia grade 3.9Tristram A Hurt CN Madden T et al.Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2014; (published online Oct 8.)http://dx.doi.org/10.1016/S1470-2045(14)70456-5PubMed Google Scholar Good responses were recorded with both drugs, with complete responses noted in 41 (46%) of 89 patients allocated cidofovir and in 42 (46%) of 91 patients assigned imiquimod. Distinct toxic-effect profiles generally seemed to favour cidofovir. Toxic effects of grade 3 or higher were noted in 39 (46%) of 84 patients treated with imiquimod and in 31 (37%) of 84 patients treated with cidofovir. However, the study was not powered to compare efficacy or toxic effects of the two treatment regimens, and comparisons are exploratory. The authors also analysed potential predictive markers, but none of them, including HPV, was associated with treatment response. HPV-negative lesions—albeit only in 12 of 15 patients—showed a better response to topical treatment than did HPV-positive lesions. Unfortunately, Tristram and colleagues did not establish pathologically whether HPV-negative lesions were differentiated vulval intraepithelial neoplasia.Currently, no topical drug is approved for treatment of vulval intraepithelial neoplasia. Tristram and colleagues' findings9Tristram A Hurt CN Madden T et al.Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2014; (published online Oct 8.)http://dx.doi.org/10.1016/S1470-2045(14)70456-5PubMed Google Scholar not only support use of imiquimod in women with vulval high-grade squamous intraepithelial lesions but also add cidofovir as a potential therapeutic option. Implementation of cidofovir in clinical practice will be indicated mainly by the durability of treatment response, which probably depends on HPV clearance. The therapeutic effect of cidofovir seems to be both antiviral and cytotoxic, which could potentially benefit immunocompromised patients; a reasonable response to cidofovir has been reported in HIV-positive patients with anal and vulvar high-grade squamous intraepithelial lesions.10Stier EA Goldstone SE Einstein MH et al.Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women.AIDS. 2013; 27: 545-551Crossref PubMed Scopus (39) Google Scholar The primary endpoint of Tristram and colleagues' study was a complete response 6 weeks after treatment; since further follow-up is still ongoing, the long-term efficacy of cidofovir remains to be proven.In the future, topical treatments could evolve to become the treatment of choice for people with high-grade squamous intraepithelial lesions, with cold-knife resection and laser vaporisation reserved for patients not responding to initial treatment. Until results of phase 3 studies comparing these different treatment modalities are available, the choice of treatment will mainly be based on the individual patient's preference.We declare no competing interests. The incidence of intraepithelial neoplasia of the vulva has been rising for the past few decades,1Judson PL Habermann EB Baxter NN Durham SB Virnig BA Trends in the incidence of invasive and in situ vulvar carcinoma.Obstet Gynecol. 2006; 107: 1018-1022Crossref PubMed Scopus (343) Google Scholar possibly due to an increase of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesions, particularly in young women. High-grade squamous intraepithelial lesions (vulval intraepithelial neoplasia grade 2–3) are typically multifocal and judged to cause more than 90% of all diagnosed cases of vulval intraepithelial neoplasia. By contrast with low-grade squamous intraepithelial lesions (vulval intraepithelial neoplasia grade 1–2), which are usually self-limiting with a high rate of spontaneous regression, high-grade squamous intraepithelial lesions can progress to invasive carcinoma and are, therefore, defined as precancerous lesions. Untreated patients have a 6–9% risk of progression to vulval carcinoma.2van Seters M van Beurden M de Craen AJ Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.Gynecol Oncol. 2005; 97: 645-651Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 3van de Nieuwenhof HP Massuger LF van der Avoort IA et al.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age.Eur J Cancer. 2009; 45: 851-856Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar Differentiated disease is another type of high-grade vulval intraepithelial neoplasia: it is less frequently diagnosed than high-grade squamous intraepithelial lesions (diagnosed in 2–10% of cases), lesions are usually HPV-negative, and the disease is typically associated with vulval lichen sclerosus.4van den Einden LC van der Avoort IA de Hullu JA Prevention, identification and treatment of vulvar squamous (pre)malignancies: a review focusing on quality of care.Exp Rev Anticancer Ther. 2013; 13: 845-859Crossref PubMed Scopus (6) Google Scholar Although HPV-negative lesions are widely accepted to have greater potential to progress to invasive disease than other lesion types (up to 30% higher),3van de Nieuwenhof HP Massuger LF van der Avoort IA et al.Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age.Eur J Cancer. 2009; 45: 851-856Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar no predictive markers are known for the progressive potential of different types of vulval intraepithelial neoplasia. Standard treatment for high-grade squamous intraepithelial lesions is surgery, either cold-knife resection or laser vaporisation, which can result in substantial morbidity and potential psychosexual dysfunction.5Thuesen B Andreasson B Bock JE Sexual function and somatopsychic reactions after local excision of vulvar intra-epithelial neoplasia.Acta Obstet Gynecol Scand. 1992; 71: 126-128Crossref PubMed Scopus (57) Google Scholar The main argument for cold-knife resection over the otherwise less invasive surgical technique of laser vaporisation is possible histological detection of occult vulvar carcinoma within a preinvasive lesion. However, in a systematic review, occult invasive disease was noted in 3% of patients, who had mostly microinvasive cancers.2van Seters M van Beurden M de Craen AJ Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.Gynecol Oncol. 2005; 97: 645-651Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar This relatively low risk shifts the focus of management of high-grade squamous intraepithelial lesions away from detection of invasive cancer and towards symptom control and prevention of carcinogenesis. 20–30% of patients who undergo a surgical intervention have recurrence of disease, irrespective of the treatment modality,6Hillemanns P Wang X Staehle S Michels W Dannecker C Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy.Gynecol Oncol. 2006; 100: 271-275Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar and neither cold-knife nor laser surgery can treat effectively the underlying cause of most high-grade squamous intraepithelial lesions—HPV infection.7Woelber L Kock L Gieseking F et al.Clinical management of primary vulvar cancer.Eur J Cancer. 2011; 47: 2315-2321Summary Full Text Full Text PDF PubMed Scopus (78) Google Scholar Topical treatment with the immune-modifier imiquimod is an effective alternative to surgery, with a durable complete response reported in 35% of patients and a partial response in 38%.8van Seters M van Beurden M ten Kate FJ et al.Treatment of vulvar intraepithelial neoplasia with topical imiquimod.N Engl J Med. 2008; 358: 1465-1473Crossref PubMed Scopus (266) Google Scholar Side-effects of imiquimod are pain and discomfort in the treatment area, fatigue, and headache. Therefore, alternative topical regimens with favourable toxic-effect profiles are needed. In The Lancet Oncology, Amanda Tristram and colleagues present findings of a randomised phase 2 trial of topical imiquimod and the nucleotide analogue cidofovir for treatment of vulval intraepithelial neoplasia grade 3.9Tristram A Hurt CN Madden T et al.Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2014; (published online Oct 8.)http://dx.doi.org/10.1016/S1470-2045(14)70456-5PubMed Google Scholar Good responses were recorded with both drugs, with complete responses noted in 41 (46%) of 89 patients allocated cidofovir and in 42 (46%) of 91 patients assigned imiquimod. Distinct toxic-effect profiles generally seemed to favour cidofovir. Toxic effects of grade 3 or higher were noted in 39 (46%) of 84 patients treated with imiquimod and in 31 (37%) of 84 patients treated with cidofovir. However, the study was not powered to compare efficacy or toxic effects of the two treatment regimens, and comparisons are exploratory. The authors also analysed potential predictive markers, but none of them, including HPV, was associated with treatment response. HPV-negative lesions—albeit only in 12 of 15 patients—showed a better response to topical treatment than did HPV-positive lesions. Unfortunately, Tristram and colleagues did not establish pathologically whether HPV-negative lesions were differentiated vulval intraepithelial neoplasia. Currently, no topical drug is approved for treatment of vulval intraepithelial neoplasia. Tristram and colleagues' findings9Tristram A Hurt CN Madden T et al.Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial.Lancet Oncol. 2014; (published online Oct 8.)http://dx.doi.org/10.1016/S1470-2045(14)70456-5PubMed Google Scholar not only support use of imiquimod in women with vulval high-grade squamous intraepithelial lesions but also add cidofovir as a potential therapeutic option. Implementation of cidofovir in clinical practice will be indicated mainly by the durability of treatment response, which probably depends on HPV clearance. The therapeutic effect of cidofovir seems to be both antiviral and cytotoxic, which could potentially benefit immunocompromised patients; a reasonable response to cidofovir has been reported in HIV-positive patients with anal and vulvar high-grade squamous intraepithelial lesions.10Stier EA Goldstone SE Einstein MH et al.Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women.AIDS. 2013; 27: 545-551Crossref PubMed Scopus (39) Google Scholar The primary endpoint of Tristram and colleagues' study was a complete response 6 weeks after treatment; since further follow-up is still ongoing, the long-term efficacy of cidofovir remains to be proven. In the future, topical treatments could evolve to become the treatment of choice for people with high-grade squamous intraepithelial lesions, with cold-knife resection and laser vaporisation reserved for patients not responding to initial treatment. Until results of phase 3 studies comparing these different treatment modalities are available, the choice of treatment will mainly be based on the individual patient's preference. We declare no competing interests. Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trialCidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease. Full-Text PDF Open Access