Abstract
Simple SummaryVulvar tumors are sometimes difficult to distinguish from adjacent healthy tissue during surgery, causing recurrence rates of up to 40% and co-morbidity. Fluorescence-guided surgery illuminating neoplastic tissue is increasingly being used to assist surgeons for various types of cancers. As no suitable tracers are known yet for vulvar tumors, we have evaluated which proteins could be targeted for fluorescence-guided surgery. Immunohistochemistry was used to study the distribution of nine membrane proteins in healthy and (pre)malignant tissues that were consequently analyzed using quantitative image analysis. Integrin αvβ6 allowed for the most robust discrimination of VSCCs and adjacent premalignant lesions compared with surrounding healthy tissue. The use of an αvβ6 targeted near-infrared fluorescent probe for FGS of vulvar (pre)malignancies should be evaluated in future studies.Surgical removal of vulvar squamous cell carcinoma (VSCC) is associated with significant morbidity and high recurrence rates. This is at least partially related to the limited visual ability to distinguish (pre)malignant from normal vulvar tissue. Illumination of neoplastic tissue based on fluorescent tracers, known as fluorescence-guided surgery (FGS), could help resect involved tissue and decrease ancillary mutilation. To evaluate potential targets for FGS in VSCC, immunohistochemistry was performed on paraffin-embedded premalignant (high grade squamous intraepithelial lesion and differentiated vulvar intraepithelial neoplasia) and VSCC (human papillomavirus (HPV)-dependent and -independent) tissue sections with healthy vulvar skin as controls. Sections were stained for integrin αvβ6, CAIX, CD44v6, EGFR, EpCAM, FRα, MRP1, MUC1 and uPAR. The expression of each marker was quantified using digital image analysis. H-scores were calculated and percentages positive cells, expression pattern, and biomarker localization were assessed. In addition, tumor-to-background ratios were established, which were highest for (pre)malignant vulvar tissues stained for integrin αvβ6. In conclusion, integrin αvβ6 allowed for the most robust discrimination of VSCCs and adjacent premalignant lesions compared to surrounding healthy tissue in immunohistochemically stained tissue sections. The use of an αvβ6 targeted near-infrared fluorescent probe for FGS of vulvar (pre)malignancies should be evaluated in future studies.
Highlights
Vulvar squamous cell carcinoma (VSCC) is a rare type of cancer with an incidence of1.5–2.7 per 100,000 women, necessitating specialized centralized care [1]
If αvβ6 was present in healthy vulvar tissue, it was mainly located in the spinosal and basal layer of the epithelium (Figure 1A)
Αvβ6 expression was higher in normal vulvar tissues wherein sebaceous glands were present (11/15 healthy vulvar tissues) compared with vulvar tissue sections that lacked those glands. αvβ6 staining within sebaceous glands was low to moderate (Figure 1A)
Summary
Vulvar squamous cell carcinoma (VSCC) is a rare type of cancer with an incidence of1.5–2.7 per 100,000 women, necessitating specialized centralized care [1]. Vulvar squamous cell carcinoma (VSCC) is a rare type of cancer with an incidence of. For the Dutch population, this increase is mainly observed in younger women [2,3]. Human papilloma virus (HPV)-dependent VSCC (20%) are caused by high-risk HPV types, predominantly HPV16. HPV-dependent VSCC arises in the background of precursor lesions named high grade squamous intraepithelial neoplasia (HSIL). Another precursor of VSCC is differentiated vulvar intraepithelial neoplasia (dVIN), which often arises in elderly women with lichen sclerosus (LS), a chronic inflammatory skin disease. For dVIN, the cumulative risk of malignant progression to VSCC is estimated to be as high as 50%
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