Molecular landscape of vulvovaginal squamous cell carcinoma: new insights into molecular mechanisms of HPV-associated and HPV-independent squamous cell carcinoma

Salama, Abeer M.; Boroujeni, Amir Momeni; Vanderbilt, Chad; Ladanyi, Marc; Soslow, Robert A.

doi:10.1038/s41379-021-00942-3

Cited by 19 publications

(13 citation statements)

References 57 publications

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“…We set out to further characterize the largely unexplored non-HPV and non-P53 mutant VSC tumors using NGS, and found striking differences in the exome of VSC tumors when stratified by HPV and p53 status. In the HPV− VSC, we validated previous findings that these tumors usually contain more genomic alterations, especially in the CDK2NA gene, as well as with TERT, p53, and FAT1 genes when compared with HPV+ tumors (9,16). Our study also identified a novel association between HPV+ tumors and genetic alterations in KMT2C.…”

Section: Discussionsupporting

confidence: 86%

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The Genomic Landscape of Vulvar Squamous Cell Carcinoma

Corey

Wallbillich

et al. 2023

International Journal of Gynecological Pathology

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Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden—high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV−/p53wt, and HPV−/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV− tumors, 52 (78.8%) were HPV−/p53mt and 14 (21.2%) were HPV−/p53wt. The HPV−/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV−/p53wt vs 26.3% HPV+ vs. 5.8% HPV−/p53mt, q=0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV−/p53wt vs. 34.2% HPV+ vs. 7.7% HPV−/p53mt, q=0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV−/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.

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Section: Discussionsupporting

confidence: 86%

“…A recent analysis of the MSK-IMPACT database found PIK3CA mutations to be strongly associated with HPV+ tumors, a finding discordant with our study. However, their cohort included combined vulvar and vaginal cases and only contained 4 HPV+ vulvar cancers 16 . Another strength of our study is the use of WES.…”

Section: Discussionmentioning

confidence: 99%

The Genomic Landscape of Vulvar Squamous Cell Carcinoma

Corey

Wallbillich

et al. 2023

International Journal of Gynecological Pathology

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“…The basaloid histology of these unusual vulvar lesions was identical to the 5 lesions identified in this series. Remarkably, vulvar squamous carcinoma is a rare neoplasm with dual etiopathogenesis (HPV-associated and HPV-independent) and a highly similar genomic landscape (frequent TP53 , CDKN2A , and NOTCH-1 mutations) 33,34. Thus, it is plausible that both types of carcinomas also share unusual HPV-negative precursors, mimicking HPV-associated PeIN.…”

Section: Discussionmentioning

confidence: 99%

“…All the 5 unusual PeIN as well as their associated invasive carcinoma were negative for both low-risk and high-risk HPV types (6,11,16,18,31,33,34,35,39,40,42,43,44,45,51,52,53,54,56,58,59, 66, 68, 70, and 74).…”

Section: Hpv Dna Testingmentioning

confidence: 98%

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HPV-negative Penile Intraepithelial Neoplasia (PeIN) With Basaloid Features

Guerrero¹,

Trias²,

Veloza

et al. 2022

American Journal of Surgical Pathology

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Most human papillomavirus (HPV)-independent penile squamous cell carcinomas (PSCCs) originate from an intraepithelial precursor called differentiated penile intraepithelial neoplasia, characterized by atypia limited to the basal layer with marked superficial maturation. Previous studies in vulvar cancer, which has a similar dual etiopathogenesis, have shown that about one fifth of HPV-independent precursors are morphologically indistinguishable from high-grade squamous intraepithelial lesions (HSILs), the precursor of HPV-asssociated carcinomas. However, such lesions have not been described in PSCC. From 2000 to 2021, 55 surgical specimens of PSCC were identified. In all cases, thorough morphologic evaluation, HPV DNA detection, and p16, p53, and Ki-67 immunohistochemical (IHC) staining was performed. HPV-independent status was assigned based on both negative results for p16 IHC and HPV DNA. Thirty-six of the 55 PSCC (65%) were HPV-independent. An intraepithelial precursor was identified in 26/36 cases (72%). Five of them (19%) had basaloid features, morphologically indistinguishable from HPV-associated HSIL. The median age of the 5 patients was 74 years (range: 67 to 83 y). All 5 cases were p16 and DNA HPV-negative. Immunohistochemically, 3 cases showed an abnormal p53 pattern, and 2 showed wild-type p53 staining. The associated invasive carcinoma was basaloid in 4 cases and the usual (keratinizing) type in 1. In conclusion, a small proportion of HPV-independent PSCC may arise on adjacent intraepithelial lesions morphologically identical to HPVassociated HSIL. This unusual histologic pattern has not been previously characterized in detail in PSCC. p16 IHC is a valuable tool to identify these lesions and differentiate them from HPVassociated HSIL.

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