scholarly journals Integrin αvβ6 as a Target for Tumor-Specific Imaging of Vulvar Squamous Cell Carcinoma and Adjacent Premalignant Lesions

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6006
Author(s):  
Bertine W. Huisman ◽  
Merve Cankat ◽  
Tjalling Bosse ◽  
Alexander L. Vahrmeijer ◽  
Robert Rissmann ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Near Infrared ◽  
Premalignant Lesions ◽  
Vulvar Intraepithelial Neoplasia ◽  
Surgical Removal ◽  
Vulvar Squamous Cell Carcinoma ◽  
Tissue Sections ◽  
Integrin Αvβ6

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.

scholarly journals Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma

2020 ◽  
Vol 21 (14) ◽  
pp. 4880 ◽  
Author(s):  
Sebastian Zięba ◽  
Anne-Floor W. Pouwer ◽  
Artur Kowalik ◽  
Kamil Zalewski ◽  
Natalia Rusetska ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lichen Sclerosus ◽  
Intraepithelial Neoplasia ◽  
Genetic Alterations ◽  
Premalignant Lesions ◽  
Vulvar Intraepithelial Neoplasia ◽  
Vulvar Squamous Cell Carcinoma ◽  
Pathogenic Mutations

Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.

scholarly journals Vulvar intraepithelial neoplasia: Incidence and long‐term risk of vulvar squamous cell carcinoma

2020 ◽  
Vol 148 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Nikki B. Thuijs ◽  
Marc Beurden ◽  
Annette H. Bruggink ◽  
Renske D. M. Steenbergen ◽  
Johannes Berkhof ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Intraepithelial Neoplasia ◽  
Vulvar Intraepithelial Neoplasia ◽  
Vulvar Squamous Cell Carcinoma

Clinical and molecular classification of vulvar squamous pre-cancers

2019 ◽  
Vol 29 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Paul A Cohen ◽  
Lyndal Anderson ◽  
Lois Eva ◽  
James Scurry
Keyword(s):  
Squamous Cell Carcinoma ◽  
Next Generation Sequencing ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Intraepithelial Neoplasia ◽  
Vulvar Intraepithelial Neoplasia ◽  
Next Generation ◽  
Vulvar Squamous Cell Carcinoma ◽  
Increased Risk ◽  
Generation Sequencing

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.

scholarly journals CXCR4/ACKR3/CXCL12 axis in the lymphatic metastasis of vulvar squamous cell carcinoma

2021 ◽  
pp. jclinpath-2020-206917
Author(s):  
Natalia Rusetska ◽  
Kamil Kowalski ◽  
Kamil Zalewski ◽  
Sebastian Zięba ◽  
Mariusz Bidziński ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Healthy Volunteers ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lymphatic Metastasis ◽  
Therapeutic Option ◽  
Premalignant Lesions ◽  
Vulvar Squamous Cell Carcinoma ◽  
Tissue Samples ◽  
Adjacent Structures

AimsVulvar squamous cell carcinoma (VSCC) spreads early and mainly locally via direct expansion into adjacent structures, followed by lymphatic metastasis to the regional lymph nodes (LNs). In the lymphatic metastasis, cancer cells bearing CXCR4 and ACKR3 (CXCR7) receptors are recruited to the LNs that produce the CXCL12 ligand. Our study aimed to assess the role of the CXCR4/ACKR3/CXCL12 axis in VSCC progression.MethodsTumour and LN tissue samples were obtained from 46 patients with VSCC and 51 patients with premalignant vulvar lesions. We assessed CXCR4, ACKR3 and CXCL12 by immunohistochemistry (IHC) in the tissue samples. Additionally, CXCL12 levels were determined by ELISA in the sera of 23 patients with premalignant lesions, 37 with VSCC and 16 healthy volunteers.ResultsCXCR4 and ACKR3 proteins were virtually absent in vulvar precancers, while in VSCC samples the IHC staining was strong. In the LNs of patients with VSCC, 98% of metastatic cells expressed CXCR4 and 85% expressed ACKR3. Neither CXCR4 nor ACKR3 presence was correlated with tumour human papilloma virus status. Few CXCL12-positive cells were found in the analysed tissue samples, but serum CXCL12 levels were significantly increased in both patients with premalignant vulvar lesions and with VSCC compared with healthy volunteers.ConclusionsIt appears that during progression and lymphatic spread of VSCC, the CXCR4/ACKR3/CXCL12 axis is activated. Moreover, our data suggest that CXCR4 antagonists merit further attention as a possible therapeutic option in patients with VSCC.

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