Does lichen sclerosus play a central role in the pathogenesis of human papillomavirus negative vulvar squamous cell carcinoma? The itch-scratch-lichen sclerosus hypothesis

Abstract

In the past decade, two types of vulvar squamous cell carcinoma (SCC) have been delineated, Human papillomavirus (HPV) positive and negative. Clinicopathologic, virologic, cytomorphometric, and genetic differences support the view that these two types of carcinoma are fundamentally different and that HPV‐negative carcinoma is not simply carcinoma where viral DNA has not been able to be identified. The traditional view of HPV‐negative carcinoma is that it is caused by chronic tissue damage from itching and scratching. However, itching and scratching alone do not explain the close association of carcinoma with lichen sclerosus, nor the absence of such an association with other itchy conditions such as eczema or psoriasis. These observations point to a role for lichen sclerosus in the pathogenesis of vulvar carcinoma. Most observations about the etiology of lichen sclerosus can be grouped into its immunogenetic or genital predisposition, or the Köbner phenomenon. In the itch‐scratch‐lichen sclerosus hypothesis, lichen sclerosus is postulated to occur as a Köbner phenomenon in women with the susceptible immunophenotype who scratch because of genital irritants such as urine, vaginal secretions and smegma, and psychological factors. Lichen sclerosus, itself a very itchy condition, contributes to a vicious cycle of itching and scratching which leads to superimposed lichen simplex chronicus, squamous cell hyperplasia, and ultimately carcinoma. The itch‐scratch‐lichen sclerosus hypothesis reconciles the traditional itch‐scratch hypothesis with the strong clinicopathologic association of lichen sclerosus with carcinoma.

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

“…On the other hand, it might also suggest that lichen sclerosus represents a more 'active' lesion, with more evident signs of alterations, than squamous cell hyperplasia (also referred to as 'chronicus lichen simplex'). 32,33 In conclusion, we believe that the results of the present study suggest that both loss of p27 Kip1 expression and DNA-oxidative damage are separately involved in the development and progression of vulvar diseases and changes in the expression of both parameters occur at an early stage of malignant transformation. Further studies on the expression of these two markers in a larger series of vulvar lesions, including VIN3 lesions, are warranted to evaluate whether they might serve as markers of risk progression of preneoplastic vulvar lesions and to better understand their significance in terms of vulvar cancer development and of their association with the biological and clinical behavior of these cancers.…”

Clinical review of 202 patients with vulval lichen sclerosus: A possible association with psoriasis

“…According to this hypothesis, early aggressive treatment of vulval lichen sclerosus should reduce the risk of vulval cancer. 20 However, there are concerns that ultrapotent topical corticosteroids 21 or topical calcineurin inhibitors 22 might promote viral proliferation and consequently increase the risk of cancer.…”

Sentinel Lymph Node Biopsy in the Management of Vulvar Carcinoma

“…The 2 main precursor lesions for vulvar cancer are intraepithelial neoplasia secondary to human papilloma virus infection (often in younger patients 35Y65 years of age) 3 as well as squamous cell hyperplasia and atypia associated with lichen sclerosus (usually in older patients 55Y85 years old). 4 In the early part of the 20th century, vulvar cancer was in the most part fatal. Attempts to improve outcomes for patients with en bloc resection of the primary tumor and regional lymph nodes were first described by Basset 5 in 1912. In this work, Basset was acting on the Halsted concept of aggressive surgery to achieve local control.…”