Chi_Principles and Practice of Gynecologic Oncology 8e

14 SECTION 2 ■ Vulvar Cancer

2.3

c h a p t e r

Vulvar Cancer: Etiology, Risk Factors, Genetics, and Molecular Biology

Diane C. Ling and Sushil Beriwal

Nowadays, two different pathways that play a role in the devel opment of vulvar SCC are recognized: an HPV-independent and an HPV-associated pathway. The relation between HPV infection and the development of vulvar SCC is not as straightforward as in cervical cancer. Approximately 18% of vulvar SCC develops in a background of HPV (1,2). Multiple pathways can eventually lead to vulvar SCC ( Figure 2.3-1 ). Differentiated vulvar intraepithelial neoplasia (d-VIN) develops independently of HPV infection. d-VIN is associated with chronic dermatoses such as LS, lichen simplex chronicus (LSC), and lichen planus (LP) (3). The pathophysiology remains poorly understood, and the exact process of malignant transformation from LS to d-VIN to SCC has yet to be discovered. However, recent studies show a relation with TP53 mutations (3). The absolute cancer risk of d-VIN is not yet determined, and studies show a risk ranging from 33% to 86% (4). A recent cohort study by Thuijs et al shows a risk of 58.3% (5). Two other types of HPV-independent vulvar lesions have been described: the vulvar acanthosis with altered differentiation (VAAD), described by Nascimento et al in 2004, and the differ entiated exophytic vulvar intraepithelial lesion (DEVIL), described by Watkins et al in 2017 (6,7). These lesions are closely related to d-VIN, and the three entities may even coexist. This suggests that they exist on a spectrum (8). There is a significant morphologic overlap between DEVIL and VAAD and only subtle histologic dif ferences can be found, but these are often subjective (9). DEVIL and VAAD differentiate themselves from d-VIN in lacking a p53 mutation. Although data are limited, VAAD and DEVIL have proven to be precancerous lesions, preceding verrucous carcinoma and low-grade SCC, respectively (8). The etiology of LS is still unclear, but evidence suggests that it is an autoimmune disorder with genetic susceptibility factors. It mostly develops in prepubertal girls and postmenopausal women but can occur in women of all ages. The first-line treatment is with topical corticosteroids, but LS is considered an incurable disease

(10). Women with LS have an increased risk for HPV-independent vulvar cancer of approximately 5% (9,11). It is still unclear whether there is a causal relationship or if LS is merely associated with vul var SCC. It develops independent of HPV and leads mostly to ke ratinizing vulvar SCC. High-grade squamous intraepithelial lesion (HSIL), previously called usual type VIN (u-VIN) or VIN-2 and VIN-3, is an uncom mon precursor of vulvar SCC and develops in the background of a high-risk HPV infection. HPV-16 is the most common, in approximately 68% of the cases, followed by HPV-33 (19%) and HPV-18 (8%). Without treatment, it can spontaneously resolve, persist, or progress to vulvar SCC. It is associated with p16 mu tations, in contrast to d-VIN, which is often associated with p53 mutations. The absolute cancer risk is approximately 10% accord ing to a recent cohort study by Thuijs and colleagues (5). When treated, percentages drop to 3% to 5% (11). Smoking and immu nosuppression are cofactors for the development of vulvar SCC in a background of HSIL. Several vulvar dermatoses have been associated with vulvar SCC. LSC is a risk factor for vulvar SCC, but no direct association has been identified (9,12). The relationship between LP and vulvar SCC has not been well established yet. So far, there is insufficient evidence to determine whether LP is a precursor lesion (13). Although HPV DNA is associated with most high-grade in traepithelial lesions (80%), it is much less commonly seen in as sociation with invasive lesions (~20%-50%) (14). Vulvar SCC with HPV positivity is more common in younger age groups, whereas vulvar SCC with HPV negativity is more common in older women. However, in older women, the incidence of HPV-associated vulvar SCC is rising and now accounts for half of vulvar SCC, especially in women over 50 (15). Distinct genomic signatures of HPV-positive and HPV-negative vulvar SCC have been identified. HPV-positive vulvar SCC tends to have genomic alterations in the Pl3K/mTOR pathway and higher tumor mutational burden (TMB) (16). On the other hand, HPV-negative vulvar SCC has been associated with genomic alter ations in TP53, TERTp, CDKN2A, CCND1, FAT1, NOTCH1, and epidermal growth factor receptor (EGFR) (17). R eferences 1. Kortekaas KE, Bastiaannet E, van Doorn HC, et al. Vulvar cancer sub classification by HPV and p53 status results in three clinically distinct sub types. Gynecol Oncol . 2020;159(3):649-656. 2. Hinten F, Molijn A, Eckhardt L, et al. Vulvar cancer: two pathways with different localization and prognosis. Gynecol Oncol . 2018;149(2):310-317. 3. Jin C, Liang S. Differentiated vulvar intraepithelial neoplasia: a brief review of clinicopathologic features. Arch Pathol Lab Med . 2019;143(6):768-771. 4. Voss FO, Thuijs NB, Vermeulen RFM, Wilthagen EA, van Beurden M, Bleeker MCG. The vulvar cancer risk in differentiated vulvar intraepithelial neoplasia: a systematic review. Cancers (Basel) . 2021;13(24):6170. 5. Thuijs NB, van Beurden M, Bruggink AH, Steenbergen RDM, Berkhof J, Bleeker MCG. Vulvar intraepithelial neoplasia: incidence and long-term risk of vulvar squamous cell carcinoma. Int J Cancer . 2021;148(1):90-98.

HPV+

HPV−

HSIL

LS

d-VIN

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Vulvar SCC

❚ Figure 2.3-1. Pathways leading to vulvar SCC. d-VIN, differentiated vulvar intraepithelial neoplasia; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LS, lichen sclerosus; SCC, squamous cell carcinoma.