HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions.
Adult
Aged
Biomarkers, Tumor
/ analysis
Carcinoma, Squamous Cell
/ chemistry
Cell Differentiation
Cell Proliferation
Chromosome Aberrations
Cyclin-Dependent Kinase Inhibitor p16
/ analysis
Female
Humans
Keratin-17
/ analysis
Keratin-7
/ analysis
Middle Aged
Mutation
Polymorphism, Genetic
Precancerous Conditions
/ diagnosis
Tumor Microenvironment
Tumor Suppressor Protein p53
/ analysis
Uterine Cervical Neoplasms
/ chemistry
Uterine Cervical Dysplasia
/ chemistry
Journal
The American journal of surgical pathology
ISSN: 1532-0979
Titre abrégé: Am J Surg Pathol
Pays: United States
ID NLM: 7707904
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
pubmed:
14
8
2021
medline:
15
2
2022
entrez:
13
8
2021
Statut:
ppublish
Résumé
Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.
Identifiants
pubmed: 34387215
doi: 10.1097/PAS.0000000000001778
pii: 00000478-202202000-00001
doi:
Substances chimiques
Biomarkers, Tumor
0
CDKN2A protein, human
0
Cyclin-Dependent Kinase Inhibitor p16
0
KRT17 protein, human
0
KRT7 protein, human
0
Keratin-17
0
Keratin-7
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
147-158Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
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