Biomarker Expression in Multifocal Vulvar High-Grade Squamous Intraepithelial Lesions.

Nikki B Thuijs,Guus Fons,Marc Van Beurden,Linde L J Klaver,Maaike C G Bleeker,Willemijn A M Schonck,Renske D M Steenbergen

doi:10.3390/cancers13225646

Abstract

Simple SummaryIn this exploratory study, we aimed to compare biomarker profiles in patients with multiple high-risk human papillomavirus (HPV)-associated vulvar precursor lesions, which is called multifocal high-grade squamous intraepithelial lesion (HSIL). The HPV-positive HSILs were tested for HPV genotype, expression of two immunohistochemical markers p16INK4a and Ki-67, and DNA methylation of six genes. Generally, the biomarkers showed similar expression between lesions. Occasionally, marked differences were observed, indicating that not all multifocal lesions are the same. Our study contributes to a better understanding of the value of potential diagnostic, prognostic, and predictive biomarkers in patients with vulvar multifocal HSIL. Validation in larger cohorts will be important.In patients with high-grade squamous intraepithelial lesion (HSIL) of the vulva, the presence of multiple lesions, called multifocal HSIL, is common. The aim of this exploratory study was to investigate biomarker expression profiles in multifocal HSIL. In total, 27 lesions from 12 patients with high-risk human papillomavirus (HPV)-positive multifocal HSIL were tested for HPV genotype, expression of p16INK4a and Ki-67, and DNA methylation of six genes. HPV16 was found most commonly in 21 (77.8%) HSILs. In two (16.4%) patients, HPV genotype differed between the lesions. All lesions demonstrated diffuse p16INK4a staining, of which three (11.1%) were combined with patchy staining. One patient (8.3%) demonstrated markedly different DNA methylation levels between lesions. Generally, heterogeneity in methylation profiles was observed between different patients, even when other biomarkers showed similar expression. In conclusion, this study is the first to demonstrate heterogeneity of individual lesions in patients with multifocal HSIL. The studied biomarkers have the potential to refine prognostic and predictive diagnostics. Future prospective, longitudinal studies are needed to further explore the potential of a biomarker profile for management of patients with multifocal HSIL.

Highlights

High-grade vulvar intraepithelial neoplasia (VIN) is the precursor of vulvar squamous cell carcinoma (VSCC)
High-grade VIN is categorized into vulvar high-grade squamous intraepithelial lesion (HSIL), which is human papillomavirus (HPV)-associated, and differentiated VIN, which is HPV-independent and associated with lichen sclerosus (LS) [1,2,3]
HSIL, known as usual type VIN, is the most common type of VIN and occurs mainly in patients who smoke from age 35 to 50 years [4]

Summary

Introduction

High-grade vulvar intraepithelial neoplasia (VIN) is the precursor of vulvar squamous cell carcinoma (VSCC). High-grade VIN is categorized into vulvar high-grade squamous intraepithelial lesion (HSIL), which is human papillomavirus (HPV)-associated, and differentiated VIN (dVIN), which is HPV-independent and associated with lichen sclerosus (LS) [1,2,3]. HSIL, known as usual type VIN (uVIN), is the most common type of VIN and occurs mainly in patients who smoke from age 35 to 50 years [4]. The presence of multiple HSILs, a frequent finding at clinical examination, is called multifocal HSIL [5,6,7]. To confirm the clinical diagnosis and to exclude underlying invasive disease, multiple biopsies or a so-called vulvar mapping is frequently performed in patients with multifocal HSIL. Treatment options for vulvar HSIL vary from topical imiquimod to surgery, the latter often leading to somatic and psychosexual morbidity [8,9]

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