Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA

Watkins, Jaclyn C; Howitt, Brooke E.; Horowitz, Neil S.; Ritterhouse, Lauren L.; Dong, Fei; MacConaill, Laura E.; Garcia, Elizabeth; Lindeman, Neal I.; Lee, Larissa J.; Berkowitz, Ross S.; Nucci, Marisa R.; Crum, Christopher P.

doi:10.1038/modpathol.2016.187

Cited by 76 publications

(120 citation statements)

References 23 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Morphologically most of the HPV À , TP53 wild-type precursors were diagnosed as dVIN and VAAD. A recent report, supportive of our findings, also identified HPV À and TP53 wild-type VCs and describe frequent activating PIK3CA mutations (73%) in this subset of cancers (40). We identified two PIK3CA mutations in our VCs (2/28, 7.1%).…”

Section: Discussionsupporting

confidence: 73%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

126

167

View full text Add to dashboard Cite

Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPVnegative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P ¼ 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV þ , HPV À /p53wt, HPV À /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV þ , 16.3% for HPV À /p53wt and 22.6% for HPV À /p53abn tumors (P ¼ 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P ¼ 0.020).Conclusions: HPV À and HPV þ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV À /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV þ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.

show abstract

Section: Discussionsupporting

confidence: 73%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

126

167

View full text Add to dashboard Cite

show abstract

“…A recent study compared 11 cases of verrucous hyperplasia including VAAD with 14 HPV-independent keratinizing vulvar squamous cell carcinomas using next generation sequencing to sequence exons of 300 genes 38. A majority of the atypical verruciform lesions showed mutations in PIK3CA and ARID2, but no p53 mutations were identified.…”

Section: Methodsmentioning

confidence: 99%

Clinical and molecular classification of vulvar squamous pre-cancers

Cohen

Anderson

Eva

et al. 2019

Int J Gynecol Cancer

View full text Add to dashboard Cite

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.

show abstract

“…in association with verrucous carcinoma, and is recognised on the basis of acanthosis with variable verruciform architecture, loss of the granular layer with superficial epithelial pallor, and multilayered plaque‐like parakeratosis (Figure ) . These same authors, recognising the overlapping histological features with DEVIL, included VAAD as a form of DEVIL in their later study . There were two subsequent case reports of VAAD; in one, the patient did have an associated verrucous carcinoma, and this progressed to conventional VSCC and eventually anaplastic carcinoma, resulting in the death of the patient, whereas, in the other report, the authors questioned whether VAAD was a form of hyperplastic lichen sclerosus .…”

Section: Precursor Lesions Of Vsccmentioning

confidence: 99%

“…Differentiated exophytic vulvar intraepithelial lesion (DEVIL) is the name proposed for a group of atypical verruciform lesions first identified in the setting of well‐differentiated keratinising VSCC . Watkins et al .…”

Section: Precursor Lesions Of Vsccmentioning

confidence: 99%

“…(DEVIL) is the name proposed for a group of atypical verruciform lesions first identified in the setting of well-differentiated keratinising VSCC. 39 Watkins et al defined these lesions on the basis of the following features: (i) exophytic, with prominent acanthosis or verruciform hyperplasia; (ii) lacking the histomorphological features of HPV-associated HSIL (VIN2/3); and (iii) lacking sufficient basal atypia to warrant a diagnosis of dVIN (Figure 9). None of the 11 cases studied had a TP53 mutation, but PIK3CA and ARID2 mutations were common (73% and 55% of cases, respectively).…”

Section: Differentiated Exophytic Vulvar Intraepithelial Lesionmentioning

confidence: 99%

See 1 more Smart Citation

Vulval squamous cell carcinoma and its precursors

2019

View full text Add to dashboard Cite

Vulval squamous cell carcinoma (VSCC) can arise through two distinct pathways [human papillomavirus (HPV)‐associated and HPV‐independent], and these VSCC variants are recognised as different disease entities on the basis of different aetiologies, morphological features, molecular events during oncogenesis, precursor lesions, prognosis, and response to treatment. The precursor of HPV‐associated VSCC, variously referred to as high‐grade squamous intraepithelial lesion (HSIL) [vulvar intraepithelial neoplasia (VIN) 2/3] or usual‐type VIN, is morphologically identical to the more common HSIL (cervical intraepithelial neoplasia 2/3) of the cervix. The precursor lesions of HPV‐independent VSCC include differentiated VIN, differentiated exophytic vulvar intraepithelial lesion, and vulvar acanthosis with altered differentiation; these have been under‐recognised by pathologists in the past, leading to delays in treatment. This review will discuss the recent advances in diagnostic surgical pathology of VSCC and its precursors, and how these diagnoses can impact on patient management.

show abstract

Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA

Cited by 76 publications

References 23 publications

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Clinical and molecular classification of vulvar squamous pre-cancers

Vulval squamous cell carcinoma and its precursors

Contact Info

Product

Resources

About