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HPV-Positive and HPV-Negative Vulvar Squamous Cell Carcinoma Are Biologically, but Not Clinically, Distinct

Published:October 28, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.009

      ABSTRACT

      Vulvar squamous cell carcinoma (VSCC) pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remains ambiguous across studies. Here, we present a retrospective cohort analysis of 36 patients with invasive VSCC where HPV status was determined using RNA in situ hybridization (ISH) and polymerase chain reaction (PCR). Clinical annotation, p16 immunohistochemistry (IHC), programmed death ligand-1 (PD-L1) IHC, HPV16 circular E7 RNA (circE7) detection, and RNA-sequencing (RNA-seq) of the cases was performed. A combination of ISH and PCR identified 20 cases (55.6%) as HPV-positive. HPV-status did not impact overall survival (HR: 1.36, 95% CI: 0.307 to 6.037, p=0.6857) or progression-free survival (HR: 1.12, 95% CI: 0.388 to 3.22, p=0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n=23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs (circRNAs), including several circRNAs that have previously been implicated in the pathogenesis of other cancers.

      Abbreviations:

      VSCC (vulvar squamous cell carcinoma), HPV (human papillomavirus), FIGO (International Federation of Gynecology and Obstetrics), ISH (in situ hybridization), circular RNA (circRNA), PD-L1 (programmed death ligand-1), IHC (immunohistochemistry), PCR (polymerase chain reaction), RNA-sequencing (RNA-seq), FFPE (formalin fixed paraffin embedded), CPS (combined positive score), TPS (tumor proportion score), LS (lichen sclerosus), HR (hazard ratio), CI (confidence interval)
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