Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome

Tessier‐Cloutier, Basile; Pors, Jennifer; Thompson, Emily F.; Ho, Julie; Prentice, Leah M; McConechy, Melissa K.; Aguirre-Hernández, Rosalía; Miller, Ruth R.; Leung, Samuel; Proctor, Lily; McAlpine, Jessica N.; Huntsman, David G.; Gilks, C. Blake; Hoang, Lynn

doi:10.1038/s41379-020-00651-3

Cited by 51 publications

(68 citation statements)

References 52 publications

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“…(ii) p53-IHC patterns were scored as p53-mutant or p53wild-type, following recent literature [17,18]. p53mutant patterns include basal to para-basal/diffuse overexpression, basal overexpression, null-pattern, or cytoplasmic expression, and these have been reported to strongly correlate with the presence of TP53 mutations [17][18][19]. Presence of any of these patterns, therefore, can be considered supportive of a histological diagnosis of dVIN.…”

Section: Methodsmentioning

confidence: 99%

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging—observations from a bi-national ring-study

et al. 2021

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Differentiated vulvar intraepithelial neoplasia (dVIN) is a premalignant lesion that is known to progress rapidly to invasive carcinoma. Accurate histological diagnosis is therefore crucial to allow appropriate treatment. To identify reliable diagnostic features, we evaluated the inter-observer agreement in the histological assessment of dVIN, among a bi-national, multi-institutional group of pathologists. Two investigators from Erasmus MC selected 36 hematoxylin-eosin-stained glass slides of dVIN and no-dysplasia, and prepared a list of 15 histological features of dVIN. Nine participating pathologists (i) diagnosed each slide as dVIN or no-dysplasia, (ii) indicated which features they used for the diagnosis, and (iii) rated these features in terms of their diagnostic usefulness. Diagnoses rendered by > 50% participants were taken as the consensus (gold standard). p53-immunohistochemistry (IHC) was performed for all cases, and the expression patterns were correlated with the consensus diagnoses. Kappa (ĸ)-statistics were computed to measure inter-observer agreements, and concordance of the p53-IHC patterns with the consensus diagnoses. For the diagnosis of dVIN, overall agreement was moderate (ĸ = 0.42), and pair-wise agreements ranged from slight (ĸ = 0.10) to substantial (ĸ = 0.73). Based on the levels of agreement and ratings of usefulness, the most helpful diagnostic features were parakeratosis, cobblestone appearance, chromatin abnormality, angulated nuclei, atypia discernable under × 100, and altered cellular alignment. p53-IHC patterns showed substantial concordance (ĸ = 0.67) with the consensus diagnoses. Histological interpretation of dVIN remains challenging with suboptimal inter-observer agreement. We identified the histological features that may facilitate the diagnosis of dVIN. For cases with a histological suspicion of dVIN, consensus-based pathological evaluation may improve the reliability of the diagnosis.

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Section: Methodsmentioning

confidence: 99%

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging—observations from a bi-national ring-study

et al. 2021

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“…Therefore, to accurately discriminate dVIN from non-dysplastic dermatoses, p53-immunohistochemistry (IHC) is commonly used as an ancillary tool [12,13,15]. Mutant patterns of p53-expression are used to support a histological diagnosis of dVIN, as these have been reported to reflect TP53 mutations that characterize dVIN [16][17][18]. However, 17-42% of dVIN can show wild-type p53-expression, which is usually observed in non-dysplastic lesions [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

et al. 2021

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Histological diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN), the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC), can be challenging, as features of dVIN may mimic those of non-dysplastic dermatoses. To aid the diagnosis, p53-immunohistochemistry (IHC) is commonly used, and mutant expression patterns are used to support a histological diagnosis of dVIN. However, a proportion of dVIN can show wild-type p53-expression, which is characteristic of non-dysplastic dermatoses. Furthermore, recent research has identified a novel precursor of HPV-independent VSCC—the p53-wild-type differentiated exophytic vulvar intraepithelial lesion (de-VIL). Currently, there are no established diagnostic IHC-markers for p53-wild-type dVIN or de-VIL. We evaluated IHC-markers, cytokeratin 17 (CK17), and SRY-box 2 (SOX2), as diagnostic adjuncts for dVIN. For this, IHC-expression of CK17, SOX2, and p53 was studied in dVIN (n = 56), de-VIL (n = 8), and non-dysplastic vulvar tissues (n = 46). For CK17 and SOX2, the percentage of cells showing expression, and the intensity and distribution of expression were recorded. We also performed next generation targeted sequencing (NGTS) on a subset of dVIN (n = 8) and de-VIL (n = 8). With p53-IHC, 74% of dVIN showed mutant patterns and 26% showed wild-type expression. Median percentage of cells expressing CK17 or SOX2 was significantly higher in dVIN (p53-mutant or p53-wild-type) and de-VIL than in non-dysplastic tissues (p < 0.01). Diffuse, moderate-to-strong, full epithelial expression of CK17 or SOX2 was highly specific for dVIN and de-VIL. With NGTS, TP53 mutations were detected in both dVIN and de-VIL. We infer that immunohistochemical markers CK17 and SOX2, when used along with p53, may help support the histological diagnosis of dVIN.

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“…A review study published by Maia et al in 2012 highlighted the uniqueness of the Brazilian’s VSCC registry and concluded that the main prognostic factors for VSCC are mainly the patient’s age, treatment, recurrence, and survival, corroborated with the global literature at the time. Nearly a decade later, the main prognostic factors for VSCC remain virtually unchanged and features such as the patient’s age, HPV/16 status, VINs occurrence, tumor stage and grade, tumor size, depth of invasion, lymph node metastasis, stromal change, and margin status continue to be relevant [ 1 , 7 , 9 , 10 , 16 , 51 , 52 ]. As such, our analysis revealed that the patient’s age (~70 years old), therapy status (~80% of patients did not receive any therapy), VSCC stage (~87% of the tumors were VSCC I/II), FIGO stage (~25% of patients were stage IIIB), tumor recurrence (~50% of patients had recurrence), LN metastasis (~40% of patients did present LN involvement), and mortality rate (~54% of the patients died) were adequate prognostic features for selection of the study population and further correlative studies.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, to improve prognosis and quality of life for VCSS patients, less invasive therapeutic options are urgently needed. In this context, in-depth studies of the molecular mechanisms underlying VSCC development and progression are necessary to define better and more effective therapeutic options [ 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis

Ferreira

Almeida

Anjos

et al. 2021

IJMS

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The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

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Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome

Cited by 51 publications

References 52 publications

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging—observations from a bi-national ring-study

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging—observations from a bi-national ring-study

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

Assessment of TSPAN Expression Profile and Their Role in the VSCC Prognosis

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