HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications
Abstract
:1. Introduction
2. Critical Issues in Diagnosing Non-HPV-Related Cervical Lesions
HPV-Negative Cervical Cancer
- Real HPV-negative cervical cancer;
- False HPV-negative case;
- Incorrect classification of a non-cervical cancer.
- a.
- Real HPV-negative cervical cancer
- b.
- False HPV-negative case
- -
- Loss of targeted HPV DNA fragment
- -
- Low viral load in latent HPV infection
- -
- Cervical cancer caused by low-risk HPV-genotype
- -
- False negative HPV-test (incorrect sampling/pre-analytical errors)
- c.
- Incorrect classification of a non-cervical cancer
3. Classification of Endocervical Adenocarcinoma
4. Clinical Features of Human Papillomavirus-Negative Adenocarcinoma
4.1. Gastric-Type Adenocarcinoma (GCA)
4.2. Clear Cell Adenocarcinoma (CCC)
4.3. Mesonephric Adenocarcinoma
4.4. Endometrioid Adenocarcinoma (ENAC)
5. Molecular Characterization of Non-HPV Associated Adenocarcinoma
5.1. Gastric-Type Adenocarcinoma
5.2. Clear Cell Adenocarcinoma (CCC)
5.3. Mesonephric Adenocarcinoma
5.4. Endometrioid Adenocarcinoma
5.5. PD1 and PDL1 Expression in NHPVA
6. Treatment of Human Papillomavirus-Negative Cervical Cancer
6.1. Staging
- TNM and FIGO stage, including maximum tumor size and detailed description of extracervical tumor extension and nodal involvement.
- Pathological tumor type.
- Depth of cervical stromal invasion and a minimum thickness of uninvolved cervical stroma.
- Presence (or absence) of lymphovascular space involvement (LVSI).
- Presence or absence of distant metastases.
- In the early stage (T1a, T1b1, T2a1), surgical/pathological staging of pelvic lymph nodes is the gold standard to assess the prognosis and guide treatment (except for T1a1 and no LVSI).
- In locally advanced cervical cancer T1b2 and higher (except T2a1) or early stage disease with suspicious lymph nodes on imaging, positron emission tomography-computed tomography (PET-CT) or chest/abdomen computed tomography (CT) is recommended for assessment of nodal and distant disease.
- Paraaortic lymph node dissection, at least up to the inferior mesenteric artery, may be considered in locally advanced cervical cancer with negative paraaortic lymph nodes on imaging for staging purposes.
6.2. Mangement of Stage T1a
6.3. Management of Other Stages (T1b/TIV)
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Abbreviations
AKT1 | Serine-threonine protein kinase AKT1 |
APOBEC3 | Apolipoprotein B mRNA editing enzyme, catalytic subunit 3 |
ARID1A | AT-rich interactive domain-containing protein 1A |
ATM | Ataxia telangiectasia mutated |
BCOR | BCL6 corepressor |
BRCA2 | Breast cancer gene 2 |
CCC | Clear cell adenocarcinoma |
CDK12 | Cyclin dependent kinase 12 |
CDKN2A | Cyclin dependent kinase inhibitor 2 |
CIN | Cervical intraepithelial neoplasia |
CTNNB1 | Catenin Beta 1 |
DES | Diethylstilbestrol |
DNA | Deoxyribonucleic acid |
ECA | endocervical adenocarcinoma |
EGFR | Epidermal growth factor receptor |
ELF | Ets domain transcription factor |
ENAC | Endometrioid adenocarcinoma |
ERB2 | Erb-B2 receptor tyrosine kinase 2 |
FBXW7 | F-box and WD repeat domain containing 7 |
FDA | Food and Drug Administration |
FGFR2 | fibroblast growth factor receptor 2 |
FGFR4 | Fibroblast growth factor receptor 4 |
GAIS | Gastric-type adenocarcinoma in situ |
GCA | Gastric-type adenocarcinoma |
GNAS | Guanine nucleotide binding protein |
H&E | hematoxylin eosin |
HER2 | Human epidermal growth factor receptor 2 |
HLA-B | Human leukocyte antigen-B |
HPV | Human papillomavirus |
IECC | International endocervical criteria and classification |
IHC | immunohistochemistry |
ISGyP | International Society of Gynecological Pathologists |
KMT2D | Lysine methyltransferase 2D |
KRAS | Kirsten rat sarcoma |
LEGH | Lobular endocervical glandular hyperplasia |
MDA | Minimal-deviation adenocarcinoma |
MDM2 | Mouse double minute 2 |
MECOM | MDS1 and EVI1 complex locus |
MMA | DNA mismatch repair |
MRI | Magnetic resonance imaging |
MSH2 | MutS homolog 2 |
MSH6 | MutS homolog 6 |
MSI-H | microsatellite instability-high |
NGS | Next generation sequencing |
NHPVA | non-HPV adenocarcinoma |
NTRK3 | Neurotrophic receptor tyrosine kinase 3 |
p-mTOR | Phosphorylated mammalian target of rapamycin |
PCR | Polymerase chain reaction |
PD-L1 | programmed cell death ligand 1 |
PI3K-AKT | Phosphatidylinositol-3-kinase |
PIK3CA | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha |
POLE | polymerase epsilon |
PTEN | Phosphatase and tensin homolog |
PTPRS | Protein tyrosine phosphatase receptor type S |
RISH | RNA in-situ hybridization |
RNA | Ribonucleic acid |
SCC | Squamous cell carcinoma |
SLX4 | Structure-specific endonuclease subunit |
SMAD4 | Mothers against decapentaplegic homolog 4 |
SMARCA4 | SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 |
STK11 | Serine/threonine kinase 11 |
TP53 | Tumor protein p53 |
WHO | World Health Organization |
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HPVA | NHPVA | Ref. | |
---|---|---|---|
Adenocarcinoma Histology | HPV Positivity Rate (%) | ||
Usual type | 72–100 | - | [7,13,20] |
Mucinous | 83–100 | - | [7] |
Gastric type | - | 0 | [20] |
Clear cells type | - | 0–28 | [13,20,21] |
Mesonephric type | - | 0 | [7] |
Endometrioid type | - | 0–27 | [7,13,20] |
WHO 2014 | IECC 2018/WHO 2020 | |
---|---|---|
HPV-Associated (HPVA) | Non-HPV-Associated (NHPVA) | |
Usual type | Usual type | Gastric type |
Mucinous carcinoma, NOS | Villoglandular | Clear cells |
Gastric type | Mucinous, NOS | Mesonephric |
Intestinal type | Mucinous, intestinal | Endometrioid |
Signet ring cell | Invasive stratified mucin-producing | |
Villoglandular | Micropapillary | |
Endometrioid | Serous’-like | |
Clear cells | ||
Serous | ||
Mesonephric |
Genetic Mutation | Sample Size (Number of Patients) | Cases with Genetic Mutation (%) | Ref. |
---|---|---|---|
AKT1 | 11 | 33 | [54] |
ARID1A | 14 | 29 | [48] |
ARID1A | 15 | 20 | [87] |
ATM | 11 | 18 | [54] |
BRCA2 | 14 | 21 | [48] |
BRCA2 | 21 | 10 | [88] |
CDKN2A | 3 | 67 | [8] |
CDKN2A | 14 | 36 | [48] |
CDKN2A | 15 | 27 | [87] |
CDKN2A | 68 | 18 | [44] |
ELF | 11 | 18 | [54] |
ERBB2 | 68 | 9 | [44] |
ERBB3 | 21 | 10 | [88] |
ERBB3 | 68 | 10 | [44] |
FGFR4 | 21 | 14 | [88] |
GNAS | 21 | 10 | [88] |
GNAS | 68 | 9 | [44] |
HLA-B | 21 | 19 | [88] |
KMT2D | 11 | 18 | [54] |
KRAS | 3 | 33 | [8] |
KRAS | 11 | 36 | [54] |
KRAS | 68 | 17 | [44] |
MSH2 | 14 | 21 | [48] |
MSH6 | 14 | 43 | [48] |
NTRK3 | 11 | 18 | [54] |
PIK3CA | 11 | 18 | [54] |
PIK3CA | 68 | 7 | [44] |
POLE | 14 | 36 | [48] |
PTEN | 15 | 20 | [87] |
PTPRS | 21 | 19 | [88] |
SLX4 | 14 | 36 | [48] |
SLX4 | 14 | 36 | [48] |
SLX4 | 21 | 10 | [88] |
SMAD4 | 68 | 9 | [44] |
STK11 | 3 | 33 | [8] |
STK11 | 14 | 29 | [48] |
STK11 | 15 | 33 | [88] |
STK11 | 19 | 21 | [88] |
STK11 | 68 | 10 | [44] |
TP53 | 3 | 67 | [8] |
TP53 | 11 | 46 | [54] |
TP53 | 14 | 50 | [48] |
TP53 | 15 | 53 | [87] |
TP53 | 21 | 52,4 | [88] |
TP53 | 68 | 41 | [44] |
CDK12 | 15 | 7 | [87] |
ERBB2 | 15 | 13 | [87] |
MDM2 | 14 | 14 | [48] |
MECOM | 15 | 7 | [87] |
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Giannella, L.; Di Giuseppe, J.; Delli Carpini, G.; Grelloni, C.; Fichera, M.; Sartini, G.; Caimmi, S.; Natalini, L.; Ciavattini, A. HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications. Int. J. Mol. Sci. 2022, 23, 15022. https://doi.org/10.3390/ijms232315022
Giannella L, Di Giuseppe J, Delli Carpini G, Grelloni C, Fichera M, Sartini G, Caimmi S, Natalini L, Ciavattini A. HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications. International Journal of Molecular Sciences. 2022; 23(23):15022. https://doi.org/10.3390/ijms232315022
Chicago/Turabian StyleGiannella, Luca, Jacopo Di Giuseppe, Giovanni Delli Carpini, Camilla Grelloni, Mariasole Fichera, Gianmarco Sartini, Serena Caimmi, Leonardo Natalini, and Andrea Ciavattini. 2022. "HPV-Negative Adenocarcinomas of the Uterine Cervix: From Molecular Characterization to Clinical Implications" International Journal of Molecular Sciences 23, no. 23: 15022. https://doi.org/10.3390/ijms232315022