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Nectin-4 expression in vulvar squamous cell carcinoma

Frederik A Stuebs1, Antje Knöll2, Arndt Hartmann3

  • 1Department of Gynecology and Obstetrics, Bavarian Cancer Research Center (BZKF), Erlangen University Hospital, Comprehensive Cancer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitaetsstrasse 21-23, Erlangen, 91054, Germany. frederik.stuebs@uk-erlangen.de.

Virchows Archiv : an International Journal of Pathology
|March 27, 2026
PubMed

Insights

Nectin-4 is expressed in vulvar squamous cell carcinoma (VSCC), suggesting it as a potential therapeutic target for antibody-drug conjugates (ADCs). However, Nectin-4 amplification was not observed in VSCC, unlike in metastatic urothelial carcinoma.

Area of Science:

  • Gynecologic Oncology
  • Cancer Biology
  • Translational Research

Background:

  • Therapeutic options for vulvar squamous cell carcinoma (VSCC) are limited.
  • Novel treatment strategies, including immune checkpoint inhibitors (ICI) and antibody-drug conjugates (ADCs), are needed for VSCC.
  • Nectin-4 is a target for the ADC Enfortumab Vedotin (EV), approved for metastatic urothelial carcinoma (mUC), but its expression in VSCC is largely uncharacterized.

Purpose of the Study:

  • To investigate Nectin-4 expression in primary and recurrent VSCC.
  • To assess the correlation between Nectin-4 expression and clinical prognostic factors.
  • To evaluate Nectin-4 amplification in VSCC.

Main Methods:

  • Analysis of 219 formalin-fixed paraffin-embedded (FFPE) VSCC samples using next-generation tissue microarrays (ngTMA).
  • Immunohistochemistry (IHC) to assess Nectin-4 protein expression (H-score).
  • Fluorescence in situ hybridization (FISH) to evaluate Nectin-4 gene amplification.

Main Results:

  • Median Nectin-4 membranous H-score was 22.5, with 32.4% of VSCCs showing moderate to strong expression.
  • Nectin-4 expression did not significantly impact overall survival but was associated with higher rates of lymph node metastases, lymphovascular invasion, G3-grading, perineural invasion, and p16-/p53+ status in Nectin-4-negative tumors.
  • 28.8% of recurrent VSCC cases exhibited moderate to strong Nectin-4 expression. No Nectin-4 amplification was detected in any VSCC samples.

Conclusions:

  • Nectin-4 is expressed in a subset of VSCC, indicating its potential as a therapeutic target for ADCs like EV.
  • Nectin-4 expression status may correlate with adverse prognostic factors in VSCC.
  • Further preclinical and clinical studies are warranted to explore EV efficacy in VSCC treatment.
Keywords:
Antibody-drug conjugatesFluorescence in situ hybridizationImmunohistochemistryNectin-4Vulvar squamous cell carcinoma

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