Vulvovaginal cancer precursors are a burden for the patients affected and have a high psychological and sexual impact. Often, they have severe and long-lasting symptoms and their treatment is complicated. Compared with cervical lesions, they develop less frequently but their incidence has increased worldwide since the 1970s. The annual progression rate of untreated vulvar precancer to invasive cancer is at least 10%, which is higher than that of cervical lesions. Vulvar and vaginal cancers account for approximately 6% of all gynecological malignancies and no screening programs exist. (Table 1)

In the past, surgery was the treatment of choice, but with a high recurrence rate. In addition, repeated surgical procedures mutilate the vulva, causing psychosexual distress.

As a consequence, several studies were conducted in order to identify the causes of the diseases and to modify the treatment modalities. The identification of HPV, especially HPV16, 18, 33 and 31, in more than 80% of the lesions has shown the connection among patients’ immune response, persistent HPV infection and disease development.^1,2 (Table 2)

Particularly, this HPV-epithelial interaction produces lesions (usually VIN, HSIL of vulva and vagina) in which the coordinated control between viral gene expression and epithelial differentiation is broken.

In addition, less invasive treatment options, preserving anatomy were investigated. Over the last years, extensive surgery as vulvectomy was abandoned and limited surgery consisting of surgical removal only of visible lesions has been the treatment of choice. Cold knife or radiofrequency surgery or CO₂-laser vaporization have been used as a single technique or in combination. In order to increase quality of life and preserve sexual function, medical therapy with different therapeutic agents, such as 5-fluorouracil, cidofovir, interferons and indole-3-carbinol, has been proposed. Recently, imiquimod has been shown to be effective, and it is commonly used in the treatment of HPV vulvovaginal cancer precursors. However, the use of imiquimod (off-label) shows a wide range in complete response rates for HSIL of vulva and vagina - from 5 to 88% and 57 to 86% respectively. A recent trial (RT3VIN) suggests cidofovir may maintain response for longer than imiquimod, with similar low rates of adverse events. Adverse event rates indicated acceptable safety of both medications.

Nonetheless, recurrence rates after treatment, regardless of modality, are as high as 30–50%, demonstrating that current treatment options are insufficient in the long term. This is due to the different immunological response to HPV infections: presence of natural antibodies against HPV reduces the risk of recurrence by 30%.³

The new perspectives in treatment aim to modify patients’ immune response and remove the initial cause of the disease: a persistent infection of human papillomavirus. Evidence shows that the prophylactic quadrivalent HPV vaccine, as for cervical cancer precursors, also prevents HPV-related vulval and vaginal HPV-associated precancers.^4,5

Regarding cancer approach, in tumors that are confined to the vulva or perineum, the reduction of surgical extension must be achieved and the excision of the lesion, with a margin of at least 1 cm of freetissue, is generally considered to be oncologically radical. However, the different surgical techniques have not been directly compared in randomized controlled trials.

Bearing in mind that lymph nodes status represents a consistent, independent prognostic parameter in order to predict overall and progression-free survival, a strategy to minimize the morbidity incurred by groin-node dissection in patients with early clinical-stage disease is sentinel node dissection. Groin lymph node metastases are present in 20%- 35% of patients with invasive tumors clinically confined to the vulva and with clinically negative nodes. Radiation therapy may avoid the morbidity of lymph node dissection, but it is not clear whether radiation therapy can achieve the same local control rates or survival rates as lymph node dissection in early-stage disease.

In conclusion, women with vulvovaginal cancer precursors are living with chronic conditions, requiring repeated treatments which can have intolerable side effects, high recurrence rates and psychosexual impairments.⁶ The goals of treatment are reducing symptoms, reducing progression and reducing the rate of recurrence. Modulation of local immune response in favor of clearance of a persistent HPV infection is not achievable in all subjects, and this partial response limits the use of this strategy. Surgery represents the gold standard treatment in cancer and conservative approach should be achieved.

DISCLOSURE
The author has no conflict of interest to disclose.

ARTICLES INCLUDED IN THE HPW SPECIAL ISSUE ON VULVAR CANCERS:

Interview with J Bornstein. Updates on vulvar cancer: epidemiology and clinical onset.

Interview with J Bornstein. Updates on vulvar cancer: the role of HPV in the causation and prevention of vulvar cancer

F Bray. Trends in the incidence of vulvar and vaginal cancers.

SM Garland and EA Joura. The rationale for vaccination to prevent vulvar and vaginal cancers. 

JC Reutter. HPV and non-HPV related vulvar cancers: Two etiological pathways.

J Bornstein. The new terminology of vulvar intraepithelial neoplasia.

M Preti M and P. Vieira Baptista. Screening for vulvar and vaginal precancers.

PK Bhuyan. Immunotherapy: the missing piece of the vulvar HSIL management puzzle.

References

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2. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018 May 9;5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29740819

3. Stankiewicz Karita HC, Hauge K, Magaret A, et al. Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA): A Trial Protocol. JAMA Netw Open. 2019;2(4):e190819. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481452/

4. Garland SM, Joura EA, Ault KA, et al. Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age. Obstet Gynecol. 2018 Aug;132(2):261-270. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29995724

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6. Bornstein J, Bogliatto F, Haefner HK, Stockdale CK, Preti M, Bohl TG, Reutter J; ISSVD Terminology Committee. The 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar Squamous Intraepithelial Lesions. Obstet Gynecol. 2016 Feb;127(2):264-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26704327

7. Hartwig S, St Guily JL, Dominiak-Felden G et al. Estimation of the overall burden of cancers, precancerous lesions, and genital warts attributable to 9-valent HPV vaccine types in women and men in Europe. Infect Agent Cancer. 2017;12:19. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387299/