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Chapter 2.4 ■ Vulvar Cancer: Preinvasive Disease 15

6. Nascimento AF, Granter SR, Cviko A, Yuan L, Hecht JL, Crum CP. Vulvar acanthosis with altered differentiation: a precursor to verrucous car cinoma? Am J Surg Pathol . 2004;28(5):638-643. 7. Watkins JC, Howitt BE, Horowitz NS, et al. Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA. Mod Pathol . 2017;30(3):448-458. 8. Singh N, Gilks CB. Vulval squamous cell carcinoma and its precur sors. Histopathology . 2020;76(1):128-138. 9. Jenkins TM, Mills AM. Putative precancerous lesions of vulvar squa mous cell carcinoma. Semin Diagn Pathol . 2021;38(1):27-36. 10. Krapf JM, Mitchell L, Holton MA, Goldstein AT. Vulvar lichen sclero sus: current perspectives. Int J Womens Health . 2020;12:11-20. 11. van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit Rev Oncol Hematol . 2008;68(2):131-156. 12. Prieske K, Woelber L, Muallem MZ, et al. Age, treatment and prog nosis of patients with squamous cell vulvar cancer (VSCC)—analysis of the AGO-CaRE-1 study. Gynecol Oncol . 2021;161(2):442-448.

13. Halonen P, Jakobsson M, Heikinheimo O, Riska A, Gissler M, Pukkala E. Lichen sclerosus and risk of cancer. Int J Cancer . 2017;140(9): 1998-2002. 14. Brusen Villadsen A, Bundgaard-Nielsen C, Ambuhl L, et al. Preva lence and type distribution of human papillomavirus infections in Danish patients diagnosed with vulvar squamous cell tumors and precursors. Gy necol Oncol Rep . 2021;37:100828. 15. Eva LJ, Sadler L, Fong KL, Sahota S, Jones RW, Bigby SM. Trends in HPV-dependent and HPV-independent vulvar cancers: the changing face of vulvar squamous cell carcinoma. Gynecol Oncol . 2020;157(2):450-455. 16. Williams EA, Werth AJ, Sharaf R, et al. Vulvar squamous cell carci noma: comprehensive genomic profiling of HPV+ versus HPV − forms re veals distinct sets of potentially actionable molecular targets. JCO Precis Oncol . 2020;4:PO.19.00406. 17. Carlson JA, Amin S, Malfetano J, et al. Concordant p53 and mdm-2 protein expression in vulvar squamous cell carcinoma and adjacent lichen sclerosus. Appl Immunohistochem Mol Morphol . 2001;9(2):150-163.

2.4

c h a p t e r

Vulvar Cancer: Preinvasive Disease

Willemijn L. van der Kolk

The nomenclature for vulvar squamous intraepithelial lesions has changed numerous times over the years, which may lead to confu sion when reviewing older literature. The term “vulvar intraepithe lial neoplasia” (VIN) was first adopted by the International Society for the Vulvovaginal Disease (ISSVD) in 1986. It was subdivided into squamous subtype, which included VIN-1, VIN-2, and VIN-3; and nonsquamous subtype, which included Paget disease and mel anoma in situ (1). In 2004, the ISSVD proposed a revised classi fication that consisted of two VIN groups, “u-VIN, HPV related,” which was subtyped into warty, basaloid, and mixed; and “d-VIN, HPV unrelated.” The term VIN-1 was discarded as it was felt to represent only benign HPV infection and reactive changes (2). In 2012, the lower anogenital squamous terminology (LAST) for HPV-related squamous intraepithelial lesions was proposed (3). This terminology was applied to any HPV-related male or female genital tract or anal/perianal lesion and was not specific to vulvar lesions. Lesions were categorized into a two-tier system consisting of HSIL or low-grade squamous intraepithelial lesion (LSIL), and the old terminology of VIN-1, VIN-2, or VIN-3 was discarded. In 2015, the ISSVD proposed the following terminology: LSIL, HSIL, and d-VIN (4). The term LSIL encompasses flat condyloma, or HPV effect, and was previously referred to as VIN-1. LSIL is not precancerous and does not require treatment unless symptom atic. HSIL was previously called u-VIN in the 2004 ISSVD termi nology, and prior to that it was referred to as VIN-2 and VIN-3. D-VIN was previously known as VIN simplex type. LSIL is often associated with low-risk HPV subtypes (6 and 11), whereas HSIL is associated with high-risk HPV subtypes (5-7), and d-VIN is not HPV-associated. In the 2020 World Health Organization (WHO) classification of female genital tumors, there is a focus on the distinction between HPV-associated and HPV-independent VIN (8). HPV-associated VIN corresponds to LSIL (VIN-1) and HSIL (u-VIN; VIN-2 and VIN-3). The term “HPV-independent VIN” was introduced and

includes d-VIN, DEVIL, and VAAD. d-VIN is a precursor lesion to more aggressive SCC, DEVIL is a precursor to less aggressive ke ratinizing SCC, and VAAD is a precursor/risk lesion to verrucous carcinoma. Vulvar aberrant maturation (VAM) is an umbrella term that is not included in the WHO classification and is sometimes used to describe lesions such as DEVIL and VAAD that have aber rant maturation and arise from lichenoid dermatitis, but lack the basal atypia required for the diagnosis of d-VIN. According to the ISSVD, the histologic definition of d-VIN re quires basal atypia combined with negative or nonblock-positive p16 and basal overexpressed, aberrant negative, or wild-type p53 (9). It usually shows keratinizing morphology with acanthosis, ab errant rete ridge pattern, and premature maturation, often arising in a background of LS. On the other hand, HSIL usually shows warty-basaloid morphology and is nonkeratinizing. Distinguishing between HPV-associated and HPV-independent precursors has important implications for treatment and prog nosis. d-VIN and steroid-resistant VAM (HPV independent) are treated with excision, whereas HSIL (HPV dependent) may be treated with imiquimod, light amplification by stimulated emission of radiation (LASER), and excision (9). d-VIN has a higher likeli hood of progressing to invasive SCC, and HPV-independent SCC is less radiosensitive and has worse prognosis than HPV-associated SCC (10-15). R eferences 1. Klapdor R, Wölber L, Hanker L, et al. Predictive factors for lymph node metastases in vulvar cancer. An analysis of the AGO-CaRE-1 multi center study. Gynecol Oncol . 2019;154(3):565-570. 2. Sideri M, Jones RW, Wilkinson EJ, et al. Squamous vulvar intraepithe lial neoplasia: 2004 modified terminology, ISSVD vulvar oncology subcom mittee. J Reprod Med . 2005;50:807-810. 3. Darragh TM, Colgan TJ, Cox JT, et al; Members of the LAST Project Work Groups. The lower anogenital squamous terminology standardization

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