VULVAR LICHEN-SCLEROSUS AND SQUAMOUS-CELL CARCINOMA - A COHORT, CASE-CONTROL, AND INVESTIGATIONAL STUDY WITH HISTORICAL-PERSPECTIVE - IMPLICATIONS FOR CHRONIC INFLAMMATION AND SCLEROSIS IN THE DEVELOPMENT OF NEOPLASIA

The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SCC). The importa nce of chronic inflammation and scarring in oncogenesis is well recogn ized. Thirty-two patients with symptomatic vulvar LS and 60 with vulva r SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar Lichen simplex chronicu s [LSC]) were investigated with a panel of seven tissue markers and fo r DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were rev iewed. Of the cohort of symptomatic vulvar LS patients (mean/median ag e, 60 years), 9% developed VIN lesions and 21% invasive SCC; symptomat ic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 year s). Second and third primary tumors developed in three of these patien ts. Of the series of 60 patients presenting with vulvar SCCa, the clin ical setting and histological features of SCCs associated with LS were significantly distinctive compared with SCCas without LS: SCCs associ ated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventiona l SCCa type (85% v 57%; P = .02), were associated with a pi-eminent fi bromyxoid stromal response (46% v 10%; P = .004),were not associated w ith VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tu mor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF- beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to th at of acute scars and differed significantly compared with normal vulv a with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P less-than .03), and proliferative index by PCNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells Ibc]; P les s-than .003). Vulvar LS showed significantly higher expression of p53 than all three central groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 be; P less-than .008), and aneuploidy (33% v diploid co ntrols) in the absence of VIN. Comparing LS with and without associate d SCCa found significant increases in age of patients (74 v 66 years; P = .001), and DNA aneuploidy (52% v 11%; P = .0001) and no difference s in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA cont ent showed significantly elevated p53 expression (85 v 60/200 be; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an a ssociation between LS and vulvar SCC. The phenomenon of chronic inflam mation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characteri zed by clinicopathologic persistence and hypocellular fibrosis (sclero sis). A subset of vulvar SCCs is significantly associated with the pre sence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA ane uploidy. As a chronic scarring inflammatory dermatosis, vulvar LS coul d act as both ''initiator and promoter'' of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 ge ne may be involved early in this proposed pathway of carcinogenesis. C opyright (C) 1998 by W.B. Saunders Company.